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Abstract: Formation of N-alkylated α-methyltryptamine derivatives (2) was accomplished by simple reductive amination of amine (1) with ketones using catalytic hydrogenation conditions (3atm H2 and 10% Pd on carbon). This method was also applied to other primary and secondary amines using ketones and aldehydes. [Copyright &y& Elsevier]

Abstract: The Claisen rearrangement/cyclization of 5-propargyloxyindoles (2) to afford dihydropyrano[3,2-e]indoles (3) as direct precursors to tetrahydropyrano[3,2-e]indoles (1, a rotationally restricted phenolic analog of 5-hydroxyindole) was examined using either refluxing bromobenzene (156°C) or Au+1 catalysis in refluxing dioxane (101°C). This transformation was best effected using Au+1 catalysis (i.e., tris[triphenylphosphinegold(I)] oxonium tetrafluoroborate) because this method required a lower reaction temperature and gave better yields when compared to the simple thermal reaction conditions (156°C). [Copyright &y& Elsevier]

A direct, short chiral synthesis of the selective α7 nicotinic receptor agonist (-)-spiro[1-azabicyclo[2.2.2]- octane-3,5′-oxazolidin-2′-one] (AR-R17779) is presented. The key step utilized attack of the dianion of the (R)-HYTRA ester [(R)-(+)-2-hydroxy-l,2,2-triphenylethyl acetate] on qui- nuclidin-3-one, followed by a selective precipitation of the diasteriomeric tertiary alcohol that led to (S)-(-)-AR-R17779 in two additional steps. [ABSTRACT FROM AUTHOR]

Describes the synthesis of a 5-aminoindole analogs on a large scale. Reaction of pyrrole with hydroxylamine; Stability of the protecting group; Potential utility of the amine protecting group in the synthesis.

Abstract: Substituted biphenyl I (BMS-207940), a selective antagonist of the endothelin A (ETA) receptor, has been proposed for the treatment of congestive heart failure. The structure of I possesses a stereogenic axis due to the hindered rotation about the biphenyl bond in the presence of its large ortho-substituents. As a result, I exhibits atropisomerism in which two nonplanar, axially enantiomers exist, which will be generically referred to as isomers A and B. Within the pharmaceutical industry, both from a scientific and regulatory point of view, characterization of enantiomeric drugs has become an important step in the development process. To investigate the configurational stability of I atropisomers, normal phase enantiomeric LC with tandem UV and laser polarimetric detection was used under pseudo-physiological conditions: first in a simple aqueous medium at 37°C, and then in human serum at 37°C. Kinetic studies indicated that the half-life of I enantiomerization in an aqueous medium at 37°C was ca. 15h. Enantiomerization of I atropisomers was greatly accelerated in the presence of human serum and human serum albumin, and the rate of enantiomerization depended on the concentration of I. The sera-concentration-dependent enantiomerization behavior of I strongly suggests a restricted site-specific substrate/I interaction mechanism. It was therefore demonstrated that atropisomeric interconversion studies for the compound studied required consideration of temperature, presence of plasma proteins, and drug concentration to account for the kinetic data. [Copyright &y& Elsevier]

Graphical abstract Highlights • First description of the SAR that led to the discovery of VU2957 (Valiglurax). • Valiglurax is only the second mGlu4 PAM clinical candidate for Parkinson's disease. • The new series afford improvements in protein binding, half-life in vivo , CNS penetration and oral bioavailability. • Highlights subtle differences in positioning of hydrogen-bond acceptors and impact on CNS penetration/P-gp liability. Abstract This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu 4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration). [ABSTRACT FROM AUTHOR]

Previous reports from our laboratory disclosed the structure and activity of a novel 1 H -pyrazolo[4,3- b ]pyridine-3-amine scaffold ( VU8506 ) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson’s disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu 4 PAMs, leading to 9i (hmGlu 4 EC 50  = 43 nM; AhR activation = 2.3-fold). [ABSTRACT FROM AUTHOR]

Agonists at the nicotinic acetylcholine alpha 7 receptor (nAChR α7) subtype have the potential to treat cognitive deficits in patients with Alzheimer’s disease (AD) or schizophrenia. Visuo-spatial paired associates learning (vsPAL) is a task that has been shown to reliably predict conversion from mild cognitive impairment to AD in humans and can also be performed by nonhuman primates. Reversal of scopolamine-induced impairment of vsPAL performance may represent a translational approach for the development of nAChR α7 agonists. The present study investigated the effect of treatment with the acetylcholinesterase inhibitor, donepezil, or three nAChR α7 agonists, BMS-933043, EVP-6124 and RG3487, on vsPAL performance in scopolamine-treated cynomolgus monkeys. Scopolamine administration impaired vsPAL performance accuracy in a dose- and difficulty- dependent manner. The impairment of eventual accuracy, a measure of visuo-spatial learning during the task, was significantly ameliorated by treatment with donepezil (0.3 mg/kg, i.m.), EVP-6124 (0.01 mg/kg, i.m.) or BMS-933043 (0.03, 0.1 and 0.3 mg/kg, i.m.). Both nAChR α7 agonists showed inverted-U shaped dose-effect relationships with EVP-6124 effective at a single dose only whereas BMS-933043 was effective across at least a 10 fold dose/exposure range. RG3487 was not efficacious in this paradigm at the dose range examined (0.03–1 mg/kg, i.m.). These results are the first demonstration that the nAChR α7 agonists, EVP-6124 and BMS-933043, can ameliorate scopolamine-induced cognitive deficits in nonhuman primates performing the vsPAL task. [ABSTRACT FROM AUTHOR]

We describe an efficient and convergent synthesis of a series of (1′S,2R,4′S)-3H-4′-azaspiro[benzo[4,5]imidazo[2,1-b]oxazole-2,2′-bicyclo[2.2.2]octanes] displaying potency for the α7 nicotinic acetylcholine receptor (nAChR) and good selectivity vs. the related 5-HT 3A receptor. [ABSTRACT FROM AUTHOR]

The α7 nicotinic acetylcholine receptor is thought to play an important role in human cognition. Here we describe the in vivo effects of BMS-902483, a selective potent α7 nicotinic acetylcholine receptor partial agonist, in relationship to α7 nicotinic acetylcholine receptor occupancy. BMS-902483 has low nanomolar affinity for rat and human α7 nicotinic acetylcholine receptors and elicits currents in cells expressing human or rat α7 nicotinic acetylcholine receptors that are about 60% of the maximal acetylcholine response. BMS-902483 improved 24 h novel object recognition memory in mice with a minimal effective dose (MED) of 0.1 mg/kg and reversed MK-801-induced deficits in a rat attentional set-shifting model of executive function with an MED of 3 mg/kg. Enhancement of novel object recognition was blocked by the silent α7 nicotinic acetylcholine receptor agonist, NS6740, demonstrating that activity of BMS-902483 was mediated by α7 nicotinic acetylcholine receptors. BMS-902483 also reversed ketamine-induced deficits in auditory gating in rats, and enhanced ex vivo hippocampal long-term potentiation examined 24 h after dosing in mice. Results from an ex vivo brain homogenate binding assay showed that α7 receptor occupancy ranged from 64% (novel object recognition) to ~90% (set shift and gating) at the MED for behavioral and sensory processing effects of BMS-902483. [ABSTRACT FROM AUTHOR]

Adaptor-associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of serine/threonine kinases, plays a role in modulating clatherin coated endocytosis of specific surface receptors. We have demonstrated that AAK1 inhibitors are efficacious in rodent models of neuropathic pain (Kostich et al., 2016). Here we have characterized the binding properties and distribution pattern of the tritiated AAK1 radioligand, [ 3 H]BMT-046091, in rodents and cynomolgus monkeys, and used the radioligand to measure the brain target occupancy following systemic administration of AAK1 inhibitors. We have found that [ 3 H]BMT-046091 is potent and selective AAK1 inhibitor. It inhibits AAK1 phosphorylation of a peptide derived from a physiologic substrate, the μ2 subunit of the adaptor protein complex, with an IC 50 value of 2.8 nM, and is inactive at >5 μM in a panel of functional or binding assays for receptors, transporters and enzymes. [ 3 H]BMT-046091 binding in the brain is absent in the AAK1 knockout mouse, and is displaceable with a high concentration of AAK1 inhibitors in wild type mice. Specific [ 3 H]BMT-046091 binding is widespread in the brain and spinal cord with the highest density in the cortex, hippocampus, amygdala, striatum and thalamus. In the spinal cord, [ 3 H]BMT-046091 binding appears enriched in the dorsal horn superficial layers. Oral administration of LP-935509, an AAK1 inhibitor, results in a dose-dependent occupation of AAK1 binding sites in the brain and spinal cord. The increase in AAK1 binding site occupancy by LP-935509 correlates with the decrease in antinociceptive responses in the rat chronic constriction injury model of neuropathic pain. [ABSTRACT FROM AUTHOR]

An asymmetric synthesis of the major metabolite of the calcitonin gene-related peptide recepotor antagonist BMS-846372 is presented. The variously substituted cyclohepta[b]pyridine ring system represents an underexplored ring system and showed some unexpected chemistry. Reactivities of epoxide and ketone functional groups on the cycloheptane ring were extensively controlled by a remote bulky TIPS group. The rate difference of the hydrogenolysis between two diastereomeric epoxide intermediates shed some light on the mechanism of epoxide hydrogenolysis, and further, deuterium labeling studies revealed more mechanistic details on this well-known chemical transformation for the first time. [ABSTRACT FROM AUTHOR]

The alpha7 (α7) nicotinic acetylcholine receptor is a therapeutic target for cognitive disorders. Here we describe 3-(3,4-difluorophenyl)-N-(1-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrazin-2-yl)ethyl)propanamide (B-973), a novel piperazine-containing molecule that acts as a positive allosteric modulator of the α7 receptor. We characterize the action of B-973 on the α7 receptor using electrophysiology and radioligand binding. At 0.1 mM acetylcholine, 1 μM B-973 potentiated peak acetylcholine-induced currents 6-fold relative to maximal acetylcholine (3 mM) and slowed channel desensitization, resulting in a 6900-fold increase in charge transfer. The EC 50 of B-973 was approximately 0.3 μM at acetylcholine concentrations ranging from 0.03 to 3 mM. At a concentration of 1 μM, B-973 shifted the acetylcholine EC 50 of peak currents from 0.30 mM in control to 0.007 mM. B-973 slowed channel deactivation upon acetylcholine removal (τ=50 s) and increased the affinity of the α7 agonist [ 3 H]A-585539. In the absence of exogenously added acetylcholine, application of B-973 at concentrations >1 μM induced large methyllycaconitine-sensitive currents, suggesting B-973 can function as an Ago-PAM at high concentrations. B-973 will be a useful probe for investigating the biological consequences of increasing α7 receptor activity through allosteric modulation. [ABSTRACT FROM AUTHOR]

A series of phosphate and ester-based prodrugs of anilinopyrazinone 1 (BMS-665053) containing either a methylene or an (acyloxy)alkoxy linker was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent ( 1 ). The prodrugs, in general, had improved aqueous solubility and oral bioavailability compared to 1 . Prodrug 12 , which contains an (acyloxy)alkoxy linker, showed the greatest improvement in the oral bioavailability relative to the parent ( 1 ), with a seven-fold increase (from 5% to 36%) in rat pharmacokinetic studies. [ABSTRACT FROM AUTHOR]

Quinuclidine-containing spirooxazolines, as described in the previous report in this series, were demonstrated to have utility as α7 nicotinic acetylcholine receptor (α7 nAChR) partial agonists. In this work, the SAR of this chemotype was expanded to include an array of diazine heterocyclic substitutions. Many of the heterocyclic analogs were potent partial agonists of the α7 receptor, selective against other nicotinic receptors and the serotinergic 5HT 3A receptor. (1′S,3′R,4′S)-N-(6-phenylpyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine, a potent and selective α7 nAChR partial agonist, was demonstrated to improve cognition in the mouse novel object recognition (NOR) model of episodic memory. [ABSTRACT FROM AUTHOR]

We describe the synthesis of quinuclidine-containing spiroguanidines and their utility as α7 neuronal nicotinic acetylcholine receptor (nAChR) partial agonists. The convergent synthetic route developed for this study allowed for rapid SAR investigation and provided access to a structurally diverse set of analogs. A potent and selective α7 nAChR partial agonist, N‐(6‐methyl‐1,3‐benzoxazol‐2‐yl)‐3′,5′‐dihydro‐4‐azaspiro[bicyclo[2.2.2]octane‐2,4′‐imidazole]‐2′‐amine (BMS-910731, 16 ), was identified. This compound induced immediate early genes c-fos and Arc in a preclinical rodent model of α7 nAChR-derived cellular activation and plasticity. Importantly, the ability to incorporate selectivity for the α7 nACh receptor over the 5-HT 3A receptor in this series suggested a significant difference in steric requirements between the two receptors. [ABSTRACT FROM AUTHOR]

[Display omitted] In our continuing efforts to explore structure–activity relationships around the novel class of potent, isonicotinamide-based GSK3 inhibitors described in our previous report, we extensively explored structural variations around both 4/5-pyridine substitutions and the amide group. Some analogs were found to have greatly improved pTau lowering potency while retaining high kinase selectivity. In contrast to previous active compounds 1a-c , a close analog 3h did not show in vivo efficacy in a triple-transgenic mouse Alzheimer's disease model. In general, these 2‑pyridinyl amide derivatives were prone to amidase mediated hydrolysis in mouse plasma. [ABSTRACT FROM AUTHOR]

Schizophrenia is a serious illness that affects millions of patients and has been associated with N -methyl- d -aspartate receptor (NMDAR) hypofunction. It has been demonstrated that activation of metabotropic glutamate receptor 5 (mGluR5) enhances NMDA receptor function, suggesting the potential utility of mGluR5 positive allosteric modulators (PAMs) in the treatment of schizophrenia. Herein we describe the optimization of an mGluR5 PAM by replacement of a phenyl with aliphatic heterocycles and carbocycles as a strategy to reduce bioactivation in a biaryl acetylene chemotype. Replacement with a difluorocyclobutane followed by further optimization culminated in the identification of compound 32 , a low fold shift PAM with reduced bioactivation potential. Compound 32 demonstrated favorable brain uptake and robust efficacy in mouse novel object recognition (NOR) at low doses. [ABSTRACT FROM AUTHOR]

Truncation of the S3 substituent of the biaryl aminothiazine 2, a potent BACE1 inhibitor, led to a low molecular weight aminothiazine 5 with moderate activity. Despite its moderate activity, compound 5 demonstrated significant brain Aβ reduction in rodents. The metabolic instability of 5 was overcome by the replacement of the 6-dimethylisoxazole, a metabolic soft spot, with a pyrimidine ring. Thus, truncation of the S3 substituent represents a viable approach to the discovery of orally bioavailable, brain-penetrant BACE1 inhibitors. [ABSTRACT FROM AUTHOR]

Herein we describe the structure activity relationships uncovered in the pursuit of an mGluR5 positive allosteric modulator (PAM) for the treatment of schizophrenia. It was discovered that certain modifications of an oxazolidinone-based chemotype afforded predictable changes in the pharmacological profile to give analogs with a wide range of functional activities. The discovery of potent silent allosteric modulators (SAMs) allowed interrogation of the mechanism-based liabilities associated with mGluR5 activation and drove our medicinal chemistry effort toward the discovery of low efficacy (fold shift) PAMs devoid of agonist activity. This work resulted in the identification of dipyridyl 22 (BMS-952048), a compound with a favorable free fraction, efficacy in a rodent-based cognition model, and low potential for convulsions in mouse. [ABSTRACT FROM AUTHOR]

A series of pyrazinone-based compounds incorporating either carbamate or aryl ether groups was synthesized and evaluated as corticotropin-releasing factor-1 (CRF 1 ) receptor antagonists. Structure–activity relationship studies led to the identification of highly potent CRF 1 receptor antagonists 14a (IC 50 = 0.74 nM) and 14b (IC 50 = 1.9 nM). The synthesis, structure–activity relationships and in vitro metabolic stability properties of compounds in this series will be described. [ABSTRACT FROM AUTHOR]

The antidepressant activity of the N-methyl-D-aspartate (NMDA) receptor channel blocker, ketamine, has led to the investigation of negative allosteric modulators (NAMs) selective for the NR2B receptor subtype. The clinical development of NR2B NAMs would benefit from a translational pharmacodynamic biomarker that demonstrates brain penetration and functional inhibition of NR2B receptors in preclinical species and humans. Quantitative electroencephalography (qEEG) is a translational measure that can be used to demonstrate pharmacodynamic effects across species. NMDA receptor channel blockers, such as ketamine and phencyclidine, increase the EEG gamma power band, which has been used as a pharmacodynamic biomarker in the development of NMDA receptor antagonists. However, detailed qEEG studies with ketamine or NR2B NAMs are lacking in nonhuman primates. The aim of the present study was to determine the effects on the qEEG power spectra of the NR2B NAMs traxoprodil (CP-101,606) and BMT-108908 in nonhuman primates, and to compare them to the NMDA receptor channel blockers, ketamine and lanicemine. Cynomolgus monkeys were surgically implanted with EEG radio-telemetry transmitters, and qEEG was measured after vehicle or drug administration. The relative power for a number of frequency bands was determined. Ketamine and lanicemine increased relative gamma power, whereas the NR2B NAMs traxoprodil and BMT-108908 had no effect. Robust decreases in beta power were elicited by ketamine, traxoprodil and BMT-108908; and these agents also produced decreases in alpha power and increases in delta power at the doses tested. These results suggest that measurement of power spectra in the beta and delta bands may represent a translational pharmacodynamic biomarker to demonstrate functional effects of NR2B NAMs. The results of these studies may help guide the selection of qEEG measures that can be incorporated into early clinical evaluation of NR2B NAMs in healthy humans. [ABSTRACT FROM AUTHOR]

This Letter describes an efficient ring-closing metathesis approach to 2-chloro-4-amino-pyrimido[4,5- c ]azepines and 2-chloro-4-amino-pyrimido[4,5- c ]oxepines. These chlorides were applied to the synthesis of several potent γ-secretase modulators (GSMs). [ABSTRACT FROM AUTHOR]

Beginning with a diaminotriazine screening hit, several series of novel, tricyclic gamma-secretase modulators (GSMs) were designed. The SAR of several related series of GSMs is presented, and the in vivo profile of a lead molecule from the series is described. [ABSTRACT FROM AUTHOR]

Phosphodiesterase 10A (PDE10A) inhibitors increase the functionality of striatal medium spiny neurons and produce antipsychotic-like effects in rodents by blocking PDE10A mediated hydrolysis of cAMP and/or cGMP. In the current study, we characterized a radiolabeled PDE10A inhibitor, [ 3 H]BMS-843496, and developed an ex vivo PDE10 binding autoradiographic assay to explore the relationship between PDE10 binding site occupancy and the observed biochemical and behavioral effects of PDE10 inhibitors in mice. [ 3 H]BMS-843496 is a potent PDE10A inhibitor with a binding affinity (K D ) of 0.15 nM and a functional selectivity of >100-fold over other PDE subtypes tested. Specific [ 3 H]BMS-843496 binding sites were dominant in the basal ganglia, especially the striatum, with low to moderate binding in the cortical and hippocampal areas, of the mouse and monkey brain. Systemic administration of PDE10 inhibitors produced a dose- and plasma/brain concentration-dependent increase in PDE10A occupancy measured in the striatum. PDE10A occupancy was positively correlated with striatal pCREB expression levels. PDE10A occupancy was also correlated with antipsychotic-like effects measured using the conditioned avoidance response model; a minimum of ∼40% occupancy was typically required to achieve efficacy. In contrast, a clear relationship between PDE10A occupancy and catalepsy scores, a potential extrapyramidal symptom readout in rodent, was not evident. [ABSTRACT FROM AUTHOR]

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide implicated in the pathophysiology of migraine. In the course of seeking CGRP antagonists with improved oral bioavailability, metabolic stability, and pharmacokinetic properties, lower molecular weight, structurally simpler piperidine and piperazine analogs of BMS-694153 were prepared. Several were found to have nM binding affinity in vitro. The synthesis and SAR of these substituted piperidine and piperazine CGRP antagonists are discussed. [ABSTRACT FROM AUTHOR]

GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics. [ABSTRACT FROM AUTHOR]

An asymmetric synthesis of novel heterocyclic analogue of the CGRP receptor antagonist rimegepant (BMS-927711, 3) is reported. The cycloheptane ring was constructed by an intramolecular Heck reaction. The application of Hayashi-Miyaura and Ellman reactions furnished the aryl and the amine chiral centers, while the separable diastereomeric third chiral center alcohols led to both carbamate and urea analogues. This synthetic approach was applicable to both 6- and 5-membered heterocycles as exemplified by pyrazine and thiazole derivatives. [ABSTRACT FROM AUTHOR]

The synthesis, evaluation, and structure–activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype ( 7c ), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented. [ABSTRACT FROM AUTHOR]

Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK 1 R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK 1 R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK 1 R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK 1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11–84%) via dose selection. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer’s disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses. [ABSTRACT FROM AUTHOR]

This Letter describes the synthesis and structure–activity relationships of a series of furo[2,3- d ][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine 2e bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3- d ]thiazine can serve as a viable bioisostere of the known furo[3,4- d ]thiazine. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: A radioligand for measuring the density of corticotropin-releasing factor subtype-1 receptors (CRF1 receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CRF1 receptor ligands based on a core 3-(phenylamino)‐pyrazin-2(1H)-one scaffold. Methods: CRF1 receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF1 receptors (displacement of [125I]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine-18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF1 receptor density (B max) was assessed in rhesus brain cortical and cerebellum membranes with the CRF1 receptor ligand, [3H]BMS-728300. Results: The three ligands selected for development showed high binding affinity (IC 50 values, 0.3–8nM) at CRF1 receptors and moderate lipophilicity (LogD, 2.8–4.4). [3H]BMS-728300 and the two 18F-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF1 receptor B max in rhesus brain was found to be 50–120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [18F]BMS-721313, [18F]BMS-732098 and [11C]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro. Conclusions: Candidate CRF1 receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF1 receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF1 receptors. [Copyright &y& Elsevier]

Abstract: An oxidation product (5) formed during the synthesis of BIBN-4096BS (1) was found to be a potent CGRP antagonist (IC50 =0.11nM). While 5 was found to be ten-fold less potent than 1, another analog 8 with lower molecular weight containing the oxidized fragment demonstrated twenty-fold higher activity than its parent 7. Alternative conditions which preclude the formation of the oxidation product are described. The activities of 1, 5, 7 and 8 in functional cAMP assay are also discussed. [Copyright &y& Elsevier]

NMDA receptor hypofunction is hypothesized to contribute to cognitive deficits associated with schizophrenia. Since direct activation of NMDA receptors is associated with serious adverse effects, modulation of the NMDA co-agonists, glycine or D-serine, represents a viable alternative therapeutic approach. Indeed, clinical trials with glycine and D-serine have shown positive results, although concerns over toxicity related to the high-doses required for efficacy remain. Synaptic concentrations of D-serine and glycine are regulated by the amino acid transporter alanine serine cysteine transporter-1 (asc-1). Inhibition of asc-1 would increase synaptic D-serine and possibly glycine, eliminating the need for high-dose systemic D-serine or glycine treatment. In this manuscript, we characterize Compound 1 ( BMS-466442), the first known small molecule inhibitor of asc-1. Compound 1 selectively inhibited asc-1 mediated D-serine uptake with nanomolar potency in multiple cellular systems. Moreover, Compound 1 inhibited asc-1 but was not a competitive substrate for this transporter. Compound 1 is the first reported selective inhibitor of the asc-1 transporter and may provide a new path for the development of asc-1 inhibitors for the treatment of schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract: Cyclopentylamine 4 was identified as a potent dual NK1R antagonist–SERT inhibitor. This compound demonstrated significant oral activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists–SERT inhibitors may be useful in treating depression disorders. [Copyright &y& Elsevier]

Abstract: Several new potent CGRP receptor antagonists have been prepared in which the amide bond of lead compound 1 has been replaced by bioisosteric imidazole moieties. Substitution at N-1 of the imidazole was optimized to afford compounds with comparable potency to that of lead 1. Conformational restraint of the imidazole to form tetrahydroimidazo[1,5-a]pyrazine 43 gave substantially improved permeability. [Copyright &y& Elsevier]

The known interactions between the serotonergic and neurokinin systems suggest that serotonin reuptake inhibitor (SSRIs) efficacy may be improved by neurokinin-1 receptor (NK1R) antagonism. In the current studies combination of a subeffective dose of an SSRI (0.3 mg/kg fluoxetine or 0.03 mg/kg citalopram) with a subeffective dose of an NK1R antagonist (0.3 mg/kg aprepitant or 1 mg/kg CP-122,721) produced efficacy in the gerbil forced swim test (FST). Serotonin transporter (SERT) occupancy produced by 1 mg/kg fluoxetine (lowest efficacious dose) was 52 ± 5% and was reduced to 29 ± 4% at 0.3 mg/kg, a dose that was efficacious in combination with 0.3 mg/kg aprepitant or 1 mg/kg CP-122,721; the corresponding NK1R occupancies were 79 ± 4% and 61 ± 4% for aprepitant and CP-122,721, respectively. For citalopram, SERT occupancy at the lowest efficacious dose (0.1 mg/kg) was 50 ± 4% and was reduced to 20 ± 5% at 0.03 mg/kg, a dose that was efficacious when combined with aprepitant (0.3 mg/kg). Aprepitant (10 mg/kg) augmented the serotonin elevation produced by fluoxetine (1 or 10 mg/kg) in the gerbil prefrontal cortex; i.e. NK1R antagonism can modulate serotonin responses. A novel orally-available dual-acting NK1R antagonist/SERT inhibitor BMS-795176 is described; gerbil K i = 1.4 and 1 nM at NK1R and SERT, respectively. BMS-795176 was efficacious in the gerbil FST; efficacy was observed with 35 ± 3% SERT occupancy and 73 ± 3% NK1R occupancy. The interaction between NK1R antagonism and SERT inhibition to lower the SERT occupancy required for antidepressant-like efficacy suggests that BMS-795176 has the potential to improve efficacy with a reduction in SSRI-associated side effects. [ABSTRACT FROM AUTHOR]

Abstract: Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be efficacious as abortive migraine therapeutics with the absence of cardiovascular liabilities that are associated with triptans. Herein, we report the discovery of a highly potent CGRP receptor antagonist, BMS-742413, with the potential to provide rapid onset of action through intranasal delivery. The compound displays excellent aqueous solubility, oxidative stability, and toxicological profile. BMS-742413 has good intranasal bioavailability in the rabbit and shows a robust, dose-dependent inhibition of CGRP-induced increases in marmoset facial blood flow. [Copyright &y& Elsevier]

Abstract: This report describes the synthesis, structure–activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders. [Copyright &y& Elsevier]

Abstract: A series of pyrazinones were prepared and evaluated as potential CRF1R PET imaging agents. Optimization of their CRF1R binding potencies and octanol–phosphate buffer phase distribution coefficients are discussed herein. [Copyright &y& Elsevier]

Abstract: BMS-763534 is a potent (CRF1 IC50 = 0.4 nM) and selective (>1000-fold selectivity vs. all other sites tested) CRF1 receptor antagonist (pA2 = 9.47 vs. CRF1-mediated cAMP production in Y79 cells). BMS-763534 accelerated the dissociation of 125I-o-CRF from rat frontal cortex membrane CRF1 receptors consistent with a negative allosteric modulation of CRF binding. BMS-763534 produced dose-dependent increases in CRF1 receptor occupancy and anxiolytic efficacy; lowest effective anxiolytic dose = 0.56 mg/kg, PO, which was associated with 71 ± 5% CRF1 receptor occupancy of frontoparietal CRF1 receptors. Sedative/ataxic effects of BMS-763534 were only observed at high dose multiples (54–179×) relative to the lowest dose required for anxiolytic efficacy. At doses of 5- to 18-fold higher than the lowest efficacious dose in the anxiety assay, BMS-763534 shared subjective effects with the benzodiazepine chlordiazepoxide. Interestingly BMS-790318, the O-demethylated metabolite of BMS-763534, showed weak affinity for the TBOB site of the GABAA receptor (67% inhibition at 10 μM) and augmented GABA evoked currents (EC50 = 1.6 μM). Thus, the unanticipated signal in the drug discrimination assay may have resulted from an interaction of the metabolite BMS-790318 with the TBOB site on the GABAA channel where it appears to behave as an allosteric potentiator of GABA evoked currents. [Copyright &y& Elsevier]

Abstract: Various substituted indazole and benzoxazolone amino acids were investigated as d-tyrosine surrogates in highly potent CGRP receptor antagonists. Compound 3, derived from the 7-methylindazole core, afforded a 30-fold increase in CGRP binding potency compared with its unsubstituted indazole analog 1. When dosed at 0.03mg/kg SC, compound 2 (a racemic mixture of 3 and its (S)-enantiomer) demonstrated robust inhibition of CGRP-induced increases in mamoset facial blood flow up to 105min. The compound possesses a favorable predictive in vitro toxicology profile, and good aqueous solubility. When dosed as a nasal spray in rabbits, 3 was rapidly absorbed and showed good intranasal bioavailability (42%). [Copyright &y& Elsevier]

Abstract: High throughput screening led to the identification of a novel series of quinolone α7 nicotinic acetylcholine receptor (nAChR) agonists. Optimization of an HTS hit (1) led to 4-phenyl-1-(quinuclidin-3-ylmethyl)quinolin-2(1H)-one, which was found to be potent and selective. Poor brain penetrance in this series was attributed to transporter-mediated efflux, which was in turn due to high pK a. A novel 4-fluoroquinuclidine significantly lowered the pK a of the quinuclidine moiety, reducing efflux as measured by a Caco-2 assay. [Copyright &y& Elsevier]

Abstract: A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK1/SERT affinity. Optimization based on NK1/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK1/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression. [Copyright &y& Elsevier]

Calcitonin gene-related peptide (CGRP) receptor antagonistshave demonstrated clinical efficacy in the treatment of acute migraine.Herein, we describe the design, synthesis, and preclinical characterizationof a highly potent, oral CGRP receptor antagonist BMS-927711 (8). Compound 8has good oral bioavailabilityin rat and cynomolgus monkey, attractive overall preclinical properties,and shows dose-dependent activity in a primate model of CGRP-inducedfacial blood flow. Compound 8is presently in phase IIclinical trials. [ABSTRACT FROM AUTHOR]

Abstract: A series of (N-benzyl-N-phenylsulfonamido)alkyl amides were developed from classic and parallel synthesis strategies. Compounds with good in vitro and in vivo γ-secretase activity were identified and described. [Copyright &y& Elsevier]

This report describes the discovery and optimizationof a BACE-1inhibitor series containing an unusual acyl guanidine chemotype thatwas originally synthesized as part of a 6041-membered solid-phaselibrary. The synthesis of multiple follow-up solid- and solution-phaselibraries facilitated the optimization of the original micromolarhit into a single-digit nanomolar BACE-1 inhibitor in both radioligandbinding and cell-based functional assay formats. The X-ray structureof representative inhibitors bound to BACE-1 revealed a number ofkey ligand:protein interactions, including a hydrogen bond betweenthe side chain amide of flap residue Gln73 and the acyl guanidinecarbonyl group, and a cation−π interaction between Arg235and the isothiazole 4-methoxyphenyl substituent. Following subcutaneousadministration in rats, an acyl guanidine inhibitor with single-digitnanomolar activity in cells afforded good plasma exposures and a dose-dependentreduction in plasma Aβ levels, but poor brain exposure was observed(likely due to Pgp-mediated efflux), and significant reductions inbrain Aβ levels were not obtained. [ABSTRACT FROM AUTHOR]

Abstract: Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein. [Copyright &y& Elsevier]

Abstract: We have systematically studied the effects of varying the central unnatural amino acid moiety on CGRP receptor antagonist potency and CYP inhibition in a series of ureidoamides. In this Letter, we report the discovery of compound 23, a potent CGRP receptor antagonist with only weak CYP3A4 inhibition. Unlike the triptans, compound 23 did not cause active constriction of ex vivo human cerebral arteries. At doses of 0.3–1mg/kg (sc), 23 showed robust inhibition of CGRP-induced increases in marmoset facial blood flow, a validated migraine model. Ureidoamide 23 derives from a novel amino acid, 1H-indazol-5-yl substituted alanine as a tyrosine surrogate. [Copyright &y& Elsevier]