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When the nucleoside analogue acyclovir was introduced in the early 1980s, it presented a game-changing treatment modality for herpes simplex virus infections. Since then, work has been ongoing to improve the weaknesses that have now been identified: a narrow time window for therapeutic success, resistance in immunocompromised patients, little influence on frequency of recurrences, relatively fast elimination, and poor bioavailability. The present Drug Annotation focuses on the helicase-primase inhibitor pritelivir currently in development for the treatment of acyclovir-resistant HSV infections and describes how a change of the molecular target (from viral DNA polymerase to the HSV helicase-primase complex) afforded improvement of the shortcomings of nucleoside analogs. Details are presented for the discovery process leading to the final drug candidate, the pivotal preclinical studies on mechanism of action and efficacy, and on how ongoing clinical research has been able to translate preclinical promises into clinical use.

A method for forced oxidative mechanochemical degradation of active pharmaceutical ingredients (APIs) using clopidogrel hydrogensulfate as a model compound is presented. Considerable and selective formation of degradants occurs already after very short reaction times of less than 15 minutes and the nature of the products is strongly dependent on the used oxidant.

In the development of new pharmaceutical formulations it is important to consider the possible interactions between the active pharmaceutical ingredient (API) and excipients which is a well-known problem. The objective of the work presented here was to investigate such reactions by means of diffusion ordered NMR spectroscopy (DOSY). The known reaction of 5-aminosalicylic acid (5-ASA) and the excipient citric acid was studied. Three reaction products have been verified by DOSY, 1H NMR and HPLC measurements. Despite a poor separation in the DOSY diagram, the reaction products could be assign due to the processing of thoughtful selected parts of the signals. The reaction of 5-ASA with formic acid and benzocaine with dibutyl phthalate was also studied by means of DOSY experiments.

Pritelivir (AIC316, BAY 57-1293) was discovered as a highly potent drug against herpes simplex viruses with a novel mode of action, i.e. inhibition of the viral helicase–primase. A side by side comparison of the oral form against Valtrex™ in patients with genital herpes, showed superiority in phase II testing for Pritelivir. A number of different solid forms have been generated for additional, e.g. systemic, or topical applications.

Pain is the most common reason for patients seeking medical care resulting in an estimated world market for analgesics of more than USD 50 billion. Pain is a highly complex, heterogeneous and dynamic process characterized by specific patterns of phenotypic sensory neuronal change. Current treatment options for pain include opioids and non-opioid analgesics, acetaminophen and non-steroidal anti-inflammatory drugs and other drug classes such as antidepressants and anticonvulsants and a combination thereof. Novel approaches are focusing on the optimization of side-effect profiles of opioid based analgesics, the improvement of selectivity for specific opioid receptors, or by addressing molecular gateways implicated in pain. Promising candidates in development target various types of voltage-gated ion channels and receptors for capsaicin and analogs. Currently, after decades of pain research it has to be stated that the assessment, prevention and treatment of pain in industrialized countries as well as in low-income and middle-income countries are neither adequate nor equitable. Further research is needed so that specifically chronic pain control can be improved and individualized.

While opioids are potent analgesics widely used in the management of pain, a number of well-known adverse effects limit their use. The sigma-1 receptor is a ligand-regulated molecular chaperone involved in pain processing, including modulation of opioid antinociception. However, data supporting the potential use of sigma-1 receptor ligands as suitable opioid adjuvants are based on studies that use non selective ligands. Also, safety issues derived from combination therapy are poorly addressed. In this study we used the new selective sigma-1 receptor antagonist S1RA (E-52862) to characterize the effect of selective sigma-1 receptor blockade on opioid-induced efficacy- and safety-related outcomes in mice. S1RA (40 mg/kg) had no effect in the tail-flick test but did enhance the antinociceptive potency of several opioids by a factor between 2 and 3.3. The potentiating effect of S1RA on morphine antinociception did not occur in sigma-1 receptor knockout mice, which supports the selective involvement of the sigma-1 receptor. Interestingly, S1RA co-administration restored morphine antinociception in tolerant mice and reverted the reward effects of morphine in the conditioned place preference paradigm. In addition, enhancement of antinociception was not accompanied by potentiation of other opioid-induced effects, such as the development of morphine analgesic tolerance, physical dependence, inhibition of gastrointestinal transit, or mydriasis. The use of sigma-1 receptor antagonists as opioid adjuvants could represent a promising pharmacological strategy to enhance opioid potency and, most importantly, to increase the safety margin of opioids. S1RA is currently in phase II clinical trials for the treatment of several pain conditions.

The addition of halides to the cationic solvate complexes of the type [Rh(PP)(solvent)2][anion] leads to the formation of trinuclear μ3-halide-bridged complexes. The corresponding complexes [Rh3(PP)3(μ3-X)2][BF4] with X = Cl or Br and diphosphines PP Me-DuPHOS, Et-DuPHOS, DIPAMP, t-Bu-BisP* and Tangphos were characterized – in most cases – also by X-ray analysis. By reducing the concentration of the active catalyst, the in situ formation of these μ-halide-bridged multinuclear complexes in catalytic reactions leads to a decrease in activity or even to a total inactivity. The required halides – in most cases chloride – are usually present as impurities in the substrates (also when produced industrially). The extent of deactivation, known from enzyme catalysis as competitive inhibition, depends on several factors: the type of halide, the ratio of stability constants of multinuclear halide complexes and of substrate complexes, and the concentration of halide and substrate in solution.

Pain is the most common reason for patients seeking medical care resulting in an estimated world market for analgesics of more than USD 50 billion. Pain is a highly complex, heterogeneous and dynamic process characterized by specific patterns of phenotypic sensory neuronal change. Current treatment options for pain include opioids and non-opioid analgesics, acetaminophen and non-steroidal anti-inflammatory drugs and other drug classes such as antidepressants and anticonvulsants and a combination thereof. Novel approaches are focusing on the optimization of side-effect profiles of opioid based analgesics, the improvement of selectivity for specific opioid receptors, or by addressing molecular gateways implicated in pain. Promising candidates in development target various types of voltage-gated ion channels and receptors for capsaicin and analogs. Currently, after decades of pain research it has to be stated that the assessment, prevention and treatment of pain in industrialized countries as well as in low-income and middle-income countries are neither adequate nor equitable. Further research is needed so that specifically chronic pain control can be improved and individualized.

Many opioid analgesics share common structural elements; however, minor differences in structure can result in major differences in pharmacological activity, pharmacokinetic profile, and clinical efficacy and tolerability.This review compares and contrasts the chemistry, pharmacodynamics, pharmacokinetics, and CNS 'functional activity' of tapentadol and tramadol, responsible for their individual clinical utilities.The distinct properties of tapentadol and tramadol generate different CNS functional activities, making each drug the prototype of different classes of opioid/nonopioid analgesics. Tramadol's analgesia derives from relatively weak µ-opioid receptor (MOR) agonism, plus norepinephrine and serotonin reuptake inhibition, provided collectively by the enantiomers of the parent drug and a metabolite that is a stronger MOR agonist, but has lower CNS penetration. Tapentadol's MOR agonist activity is several-fold greater than tramadol's, with prominent norepinephrine reuptake inhibition and minimal serotonin effect. Accordingly, tramadol is well-suited for pain conditions for which a strong opioid component is not needed-and it has the benefit of a low abuse potential; whereas tapentadol, a schedule-II controlled substance, is well-suited for pain conditions requiring a strong opioid component-and it has the benefit of greater gastrointestinal tolerability compared to classical strong opioids. Both drugs offer distinct and complementary clinical options.

On the basis of the 6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] framework, a series of more than 30 σ ligands with versatile substituents in 1-, 2'-, and 6'-position has been synthesized and pharmacologically evaluated in order to find novel structure-affinity relationships. It was found that a cyclohexylmethyl residue at the piperidine N-atom instead of a benzyl moiety led to increased σ(2) affinity and therefore to decreased σ(1)/σ(2) selectivity. Small substituents (e.g., OH, OCH(3), CN, CH(2)OH) in 6'-position adjacent to the O-atom were well tolerated by the σ(1) receptor. Removal of the substituent in 6'-position resulted in very potent but unselective σ ligands (13). A broad range of substituents with various lipophilic and H-bond forming properties was introduced in 2'-position adjacent to the S-atom without loss of σ(1) affinity. However, very polar and basic substituents in both 2'- and 6'-position decreased the σ(1) affinity considerably. It is postulated that the electron density of the thiophene moiety has a big impact on the σ(1) affinity.

The novel class of spirocyclic σ1 ligands 3 (6′,7′-dihydro-1′H-spiro[piperidine-4,4′-pyrano[4,3-c]pyrazoles]) was designed by the combination of the potent σ1 ligands 1 and 2 in one molecule. Thorough structure affinity relationships were derived by the variation of the substituents in position 1′, 1, and 6′. Whereas the small electron rich methylpyrazole heterocycle was less tolerated by the σ1 receptor protein, the introduction of a phenyl substituent instead of the methyl group led to ligands with a high σ1 affinity. It is postulated that the additional phenyl substituent occupies a previously unrecognized hydrophobic region of the σ1 receptor resulting in additional lipophilic interactions. The spirocyclic pyranopyrazoles are very selective against the σ2 subtype, the PCP binding site of the NMDA receptor, and further targets. Despite high σ1 affinity, the cyclohexylmethyl derivative 17i (Ki (σ1) = 0.55 nM) and the isopentenyl derivative 17p (Ki (σ1) = 1.6 nM) showed only low antiallodynic activity in...

Based on the pharmacophore model of Glennon the conformationally restricted σ(1) receptor ligand 2 with a 1,3-dioxane moiety has been designed and synthesized. The three step synthesis (transacetalization with pentane-1,3,5-triol, tosylation, and nucleophilic substitution with benzylamine) provided diastereoselectively the cis-configured 1,3-dioxane 2 in good yields. The 1,3-dioxane 2 represents a potent σ(1) receptor ligand (K(i) = 19 nM) with moderate selectivity over the σ(2) subtype (K(i) = 92 nM) and excellent selectivity against more than 60 other targets. Additionally the hERG K(+) channel is not affected by 2. In the capsaicin assay 2 showed extraordinarily high analgesic activity with more than 70% analgesia at the very low dose of 0.25 mg/kg body weight, which indicates σ(1) antagonistic activity. Since 2 does only interact with σ(1) receptors, the in-vivo antiallodynic activity of 2 must be attributed to the σ(1) antagonistic activity.

Paracetamol ist eines der bekanntesten und meistverbreiteten Arzneimittel. Seit vielen Jahrzehnten wird es zur Fiebersenkung und gegen leichte bis mittelstarke Schmerzen eingesetzt und ist dabei zuverlassig wirksam und gut vertraglich. Der Wirkmechanismus ist sehr komplex und beruht auf dem Zusammenspiel mehrerer Komponenten: einer Hemmung der Cyclooxygenase in Gehirn und Ruckenmark, der Aktivierung des Serotoninsystems und der Modulation des Endocannabinoidsystems. Paracetamol ist bei bestimmungsmasigem Gebrauch ein sicheres Arzneimittel. Nebenwirkungen treten deutlich seltener auf als bei vielen weitverbreiteten nichtsteroidalen Antiphlogistika.

Anti-inflammatory efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) has been related to their properties as inhibitors of cyclooxygenase (COX)-mediated prostaglandin (PG) synthesis. However, recent studies have suggested that variations of the in vivo anti-inflammatory actions among different NSAIDs could not be solely explained by COX inhibition. Here, we have analyzed the effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole anti-inflammatory drugs with different potencies as COX-2 inhibitors, namely E-6087, E-6232, E-6231, E-6036 and E-6259 as well as the chemically related COX-2 inhibitor Celecoxib. These drugs inhibited mitogen-mediated T cell proliferation as well as Interleukin (IL)-2, tumor necrosis factor (TNF)-α and Interferon (IFN)-γ synthesis by activated T cells, independently of their ability to inhibit COX-2 enzymatic activity. Immunosuppressive effects of these drugs seem to be due to their interference on transcription factor activation as induced transcription from Nuclear Factor (NF)-κB and Nuclear Factor of Activated T cells (NFAT)-dependent enhancers was inhibited in a dose-dependent manner, being the latter effect the most sensitive to the action of those compounds. Both NFAT dephosphorylation, required for its nuclear translocation, as well as transcriptional activity of a GAL4-NFAT chimera were diminished in the presence of these compounds. These findings provide new insights into the molecular mechanisms involved in the immunomodulatory and anti-inflammatory actions of NSAIDs, which may have important implications in anti-inflammatory therapy, through inhibition of NFAT.

The efficient design of stereochemically challenging ring systems by ring opening of heterobicyclic alkenes has become a very important reaction in the chemistry of C-C and C-X bond formation. By using the hitherto applied in situ technique for the generation of the μ 2 -bridged, dimeric neutral rhodium complexes, however, the catalytically active species and its concentration remained unidentified. Furthermore, the reaction temperature is at least 80°C. The application of cationic rhodium(I) solvate complexes (that no longer contain blocking diolefins) shows that a much greater activity and enantioselectivity for the synthesis of 1,2-dihydro-1-naphthols can be reached than was described so far, even at ambient temperature. NMR spectroscopy and X-ray analysis show that a product inhibition during the ring opening reaction takes place that is independent of the nucleophile.

Several voltage-gated sodium channels are expressed in primary sensory neurons where they control excitability and participate in the generation and propagation of action potentials. Peripheral nerve injury-induced alterations in both tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels have been proposed to contribute to neuropathic pain caused by such lesion. We herein investigated whether the blockade of TTX-sensitive channels could reduce pain-related behaviors and evoked c-Fos immunoreactivity in rats with neuropathic pain produced by chronic unilateral constriction injury to either the sciatic nerve or the infraorbital nerve. Acute as well as subchronic administration of TTX (1-6 mug/kg s.c.) was found to suppress for up to 3 h allodynia and hyperalgesia in sciatic nerve-ligated rats. In contrast, TTX was only moderately effective in rats with ligated infraorbital nerve. In sciatic nerve-ligated rats, TTX administration prevented the increased c-Fos immunoreactivity occurring in the dorsal horn of the lumbar cord and some supraspinal areas in response to light mechanical stimulation of the nerve-injured hindpaw. The anti-allodynia/antihyperalgesia caused by TTX in these neuropathic rats was promoted by combined treatment with naloxone (0.5 mg/kg s.c.) but unaffected by the 5-HT(1B) receptor antagonist F11648 (0.5 mg/kg s.c.) and the alpha(2)-adrenergic receptor antagonist idazoxan (0.5 mg/kg i.v.). In contrast, the anti-allodynic and anti-hyperalgesic effects of TTX were significantly attenuated by co-administration of morphine (3 mg/kg s.c.) or the cholecystokinin(2)-receptor antagonist CI-1015 (0.1 mg/kg i.p.). These results indicate that TTX alleviates pain-related behaviors in sciatic nerve-lesioned rats through mechanisms that involve complex interactions with opioidergic systems.

Objectives The pharmacology and metabolism of the potent σ1 receptor ligand 1′-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4′-piperidine] were evaluated. Methods The compound was tested against a wide range of receptors, ion channels and neurotransmitter transporters in radioligand binding assays. Analgesic activity was evaluated using the capsaicin pain model. Metabolism by rat and human liver microsomes was investigated, and the metabolites were identified by a variety of analytical techniques. Key findings 1′-Benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4′-piperidine] (compound 1) is a potent σ1 receptor ligand (Ki 1.14 nM) with extraordinarily high σ1/σ2 selectivity (>1100). It was selective for the σ1 receptor over more than 60 other receptors, ion channels and neurotransmitter transporters, and did not interact with the human ether-a-go-go-related gene (hERG) cardiac potassium channel. Compound 1 displayed analgesic activity against neuropathic pain in the capsaicin pain model (53% analgesia at 16 mg/kg), indicating that it is a σ1 receptor antagonist. It was rapidly metabolised by rat liver microsomes. Seven metabolites were unequivocally identified; an N-debenzylated metabolite and a hydroxylated metabolite were the major products. Pooled human liver microsomes formed the same metabolites. Studies with seven recombinant cytochrome P450 isoenzymes revealed that CYP3A4 produced all the metabolites identified. The isoenzyme CYP2D6 was inhibited by 1 (IC50 88 nM) but did not produce any metabolites. Conclusions 1′-Benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4′-piperidine] is a potent and selective σ1 receptor antagonist, which is rapidly metabolised. Metabolically more stable σ1 ligands could be achieved by stabilising the N-benzyl substructure.

This work aimed to evaluate the potential role of the 5-HT(7) receptor in nociception secondary to a sensitizing stimulus in mice. For this purpose, the effects of relevant ligands (5-HT(7) receptor agonists: AS-19, MSD-5a, E-55888; 5-HT(7) receptor antagonists: SB-258719, SB-269970; 5-HT(1A) receptor agonist: F-13640; 5-HT(1A) receptor antagonist: WAY-100635) were assessed on capsaicin-induced mechanical hypersensitivity, a pain behavior involving hypersensitivity of dorsal horn neurons (central sensitization). For the 5-HT(7) receptor agonists used, binding profile and intrinsic efficacy to stimulate cAMP formation in HEK-293F cells expressing the human 5-HT(7) receptor were also evaluated. AS-19 and E-55888 were selective for 5-HT(7) receptors. E-55888 was a full agonist whereas AS-19 and MSD-5a behaved as partial agonists, with maximal effects corresponding to 77% and 61%, respectively, of the cAMP response evoked by the full agonist 5-HT. Our in vivo results revealed that systemic administration of 5-HT(7) receptor agonists exerted a clear-cut dose-dependent antinociceptive effect that was prevented by 5-HT(7) receptor antagonists, but not by the 5-HT(1A) receptor antagonist. The order of efficacy (E-55888>AS-19>MSD-5a) matched their in vitro efficacy as 5-HT(7) receptor agonists. Contrary to agonists, a dose-dependent promotion of mechanical hypersensitivity was observed after administration of 5-HT(7) receptor antagonists, substantiating the involvement of the 5-HT(7) receptor in the control of capsaicin-induced mechanical hypersensitivity. These findings suggest that serotonin exerts an inhibitory role in the control of nociception through activation of 5-HT(7) receptors, and point to a new potential therapeutic use of 5-HT(7) receptor agonists in the field of analgesia.

We investigated the function and expression of voltage-gated Na+ channels (VGSC) in the uteri of nonpregnant rats using organ bath techniques, intracellular [Ca2+] fluorescence measurements, and RT-PCR. In longitudinally arranged whole-tissue uterine strips, veratridine, a VGSC activator, caused the rapid appearance of phasic contractions of irregular frequency and amplitude. After 50–60 min in the continuous presence of veratridine, rhythmic contractions of very regular frequency and slightly increasing amplitude occurred and were sustained for up to 12 h. Both the early and late components of the contractile response to veratridine were inhibited in a concentration-dependent manner by tetrodotoxin (TTX). In small strips dissected from the uterine longitudinal smooth muscle layer and loaded with Fura-2, veratridine also caused rhythmic contractions, accompanied by transient increases in [Ca2+]i, which were abolished by treatment with 0.1 μM TTX. Using end-point and real-time quantitative RT-PCR,...

Amino acid derived 3-pyrrolines can be readily prepared in a single step in enantiomerically pure form by cycloalkylation of the corresponding amino esters with (Z)-1,4-dichloro-2-butene. Enantiopure azabicyclo[3.3.0]octenones can be then easily obtained through an unprecedented Pauson-Khand reaction followed by diastereomer separation.

Novel antiviral drugs, which are less prone to resistance development, are desirable alternatives to the currently approved drugs for the treatment of potentially serious influenza virus infections. The viral polymerase is highly conserved and serves as an attractive target for antiviral drugs since potent inhibitors would directly stop viral replication at an early stage. Recent structural studies on the functional domains of the heterotrimeric influenza polymerase, which comprises subunits PA, PB1, and PB2, opened the way to a structure-based approach for optimizing inhibitors of viral replication. These strategies, however, are limited by the use of isolated protein fragments instead of employing the entire ribonucleoprotein complex (RNP), which represents the functional form of the influenza polymerase in infected cells. In this study, we have established a screening assay for efficient and reliable analysis of potential influenza polymerase inhibitors of various molecular targets such as monoselective polymerase inhibitors targeting the endonuclease site, the cap-binding domain, and the polymerase active site, respectively. By utilizing whole viral RNPs and a radioactivity-free endpoint detection with the capability for efficient compound screening while offering high-content information on potential inhibitors to drive medicinal chemistry program in a reliable manner, this biochemical assay provides significant advantages over the currently available conventional assays. We propose that this assay can eventually be adapted for coinstantaneous analysis and subsequent optimization of two or more different chemical scaffold classes targeting multiple active sites within the polymerase complex, thus enabling the evaluation of drug combinations and characterization of molecules with dual functionality.

1 E-6837 is a novel, selective and high-affinity 5-HT6 receptor ligand (pKi: 9.13) which in vitro demonstrates partial agonism at a presumably silent rat 5-HT6 receptor and full agonism at a constitutively active human 5-HT6 receptor by monitoring the cAMP signaling pathway. 2 The effects of chronic treatment with E-6837 were determined in diet-induced obese (DIO)-rats on changes in body weight, food and water intake, plasma indices of comorbid risk factors, and weight regain on compound withdrawal. The centrally acting antiobesity drug, sibutramine, was used as the reference comparator. 3 Sustained body weight loss and decreased cumulative food intake of DIO-rats was observed with E-6837 (30 mg kg−1, p.o., twice a day) during the 4-week treatment period. The onset of the E-6837 effect on body weight was slower than that of sibutramine (5 mg kg−1, p.o.), while its maximal effect was greater, that is −15.7 versus −11.0%. 4 E-6837-induced weight loss was exclusively mediated by a decrease (31.7%) in fat mass, with a concomitant reduction (49.6%) in plasma leptin. Reduced obesity was also reflected in improved glycemic control. 5 Although weight regain occurred after withdrawal from either compound, the body weights after E-6837 (−6.6%) remained lower than after sibutramine (−3.8%) indicating that the greater efficacy of the former did not result in profound rebound hyperphagia/weight gain. 6 These results show that the 5-HT6 receptor partial agonist, E-6837, is a promising new approach to the management of obesity with the potential to produce greater sustained weight loss than sibutramine. British Journal of Pharmacology (2006) 148, 973–983. doi:10.1038/sj.bjp.0706807

1 Two novel selective 5-HT6 receptor ligands E-6801 (6-chloro-N-(3-(2-(dimethylamino)ethyl)-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide) and E-6837 (5-chloro-N-(3-(2-(dimethylamino)ethyl)-1H-indol-5-yl)naphthalene-2-sulfonamide) were investigated and compared to the putative 5-HT6 receptor antagonists SB-271046 (5-chloro-N-(4-methoxy-3-(piperazin-1-yl)phenyl)-3-methylbenzo[b]thiophene-2-sulfonamide) and Ro 04-06790 (N-(2,6-bis(methylamino)pyrimidin-4-yl)-4-aminobenzenesulfonamide) using a cAMP-mediated pathway. 2 Forskolin stimulation, to increase the magnitude of agonist cAMP responses, and site-directed mutagenesis of the 5-HT6 receptor, in order to yield constitutively active receptor, were applied. 3 5-HT (Emax, % over basal: 200), E-6801 (120) and E-6837 (23) induced cAMP formation at the rat 5-HT6 receptor. In the copresence of forskolin, cAMP responses were more potent and enhanced to 294 (5-HT, % over forskolin), 250 (E-6801) and 207 (E-6837), respectively. 5-HT-mediated cAMP formation was dose-dependently blocked by SB-271046 (pA2: 8.76±0.22) and Ro 04-6790 (pA2: 7.89±0.10) and not affected by the copresence of forskolin. Both E-6801 and E-6837 yielded partial antagonism of the 5-HT response in the absence of forskolin, whereas antagonism was either completely absent (E-6801) or attenuated (E-6837) in the copresence of forskolin. Intrinsic activity of these 5-HT6 receptor ligands at a constitutively active human S267K 5-HT6 receptor in Cos-7 cells indicated similar efficacy (Emax, % over basal) for 5-HT (97), E-6801 (91) and E-6837 (100), while Ro 04-6790 (-33) and SB-271046 (-39) were equi-efficacious inverse agonists. 4 The use of either forskolin or a constitutively active S267K 5-HT6 receptor enhances the resolution for monitoring the efficacy of 5-HT6 receptor ligands. E-6801 and E-6837 are potent partial agonists at the 5-HT6 receptor. Ro 04-6790 and SB-271046 appear to act as inverse agonists/antagonists. British Journal of Pharmacology (2006) 148, 1133–1143. doi:10.1038/sj.bjp.0706827

Asymmetric hydrogenation of (Z)-2-benzoylamino-3-(3,4-dimethoxyphenyl)-methyl acrylate with [Rh((S,S)-DIPAMP)(MeOH)2]BF4 was investigated. Low temperature NMR measurements prove the recently publis...

Screening of our internal chemical collection against the neuropeptide Y5 (NPY Y5) receptor allowed the identification of a benzoxazine derivative 5f as a hit that showed moderate affinity (IC(50) = 300 nM). With the aim of improving the in vitro potency, a series of 2-benzoxazinone derivatives have been synthesized and tested for NPY Y5 activity. Most of the compounds were found to be potent and selective NPY Y5 antagonists having nanomolar binding affinities for the NPY Y5 receptor and showing functional antagonism in the forskolin-induced cyclic AMP test. Prelimminary studies in order to understand the structure-activity relationship were undertaken. Selected compounds were further evaluated for in vivo efficacy, affording the lead compound 2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)acetamide 5p, which displayed in vivo activity reducing food intake in rodents.

Sulfoximine- and sulfilimine-based diamino-diphenyl sulfone (DAPSON) analogues have been prepared and their COX-1 and COX-2 inhibition potencies as well as LTB4 and TNF binding properties were studied. Furthermore, their antiproliferative activities on cancer cell growth were investigated. Neither compounds showed significant bioactivities.

Klassische Opioide entfalten ihre Wirkung uber eine agonistische Wirkung am μRezeptor, weisen bekannte Nebenwirkungen wie Atemdepression auf und stehen wegen ihres Sucht-und Abhangigkeitspotenzials zumeist unter Kontrolle der BtmVV. Gemischte Agonisten/Antagonisten und partielle Agonisten zeichnen sich dagegen durch eine Beteiligung des κ-Rezeptors an der analgetischen Wirkung und/oder durch einen partiellen Agonismus an Opiatrezeptoren aus. Diese Eigenschaften fuhren zu analgetischen Wirkstarken, die meist im Bereich des Morphins oder wie im Falle des Buprenorphins deutlich daruber liegen. Neben der analgetischen Wirkung weisen die Substanzen ein verandertes Nebenwirkungsspektrum auf, das in einigen Fallen — z.B. durch geringere Atemdepression — gunstiger ausfallt als bei den klassischen Opioiden, in anderen Fallen sogar zur fehlenden Betaubungsmittelkontrolle beitragt.

The syntheses and biological profiles of sulfoximine-based Vioxx® analogs 2 are described. Interesting data have been obtained for 2a, which shows a selective COX-2 inhibition (albeit not as strong as Vioxx® itself) exhibiting reduced hERG activity compare to the parent sulfone Vioxx® (1).

Efficient enzymatic resolutions of the analgesic δ-hydroxytramadol rac - 3 and e-hydroxytramadol rac - 4 have been achieved through pig liver esterase- and Candida rugosa lipase-catalyzed hydrolyses of the corresponding butyrates. The Candida rugosa lipase-catalyzed hydrolysis of O -desmethyltramadol butyrate rac - 8a , having a remote aromatic acyloxy group as the only functional group amendable to a hydrolase-catalyzed reaction, proceeded with a good selectivity.

The similarities and differences between nonlinear effects in asymmetric synthesis (see diagram), predicted 60 years ago by W. Langenbeck, and the long-known amplification phenomenon in stoichiometric reactions with chiral starting materials are discussed.

A straightforward synthesis of ( S )-pregabalin in 28% overall yield starting from d -mannitol acetonide, as a primary source of chirality, is presented. The process is suitable for large-scale synthesis and involves simple and high-yielding chemical transformations as well as low-cost commercially available reagents.

The analytical expression for deviations from linear behavior of logarithmic product ratios as a function of the reciprocal temperature (modified Eyring-plots) depends on the reason for the displacement. Therefore no generally valid formula exists that describes the experimentally observed inversion temperatures. In the case of the disturbance of the establishment of preequilibria, general conditions for the existence of inversion temperatures associated with maxima and minima are deduced. In addition it is shown that the inversion temperature is independent of the activation entropy values for the reaction of the starting materials to the intermediates (ΔS11‡ and ΔS12‡), but is dependent on the corresponding activation enthalpy values.The examples discussed show that the limiting conditions intersecting points of the absolute rates are not suitable for a general description of the complex behavior of the nonlinear temperature dependency.

The influence of the temperature on selectivity is described under special consideration of nonlinearities in the corresponding modified Eyring plots. Reasons for the experimentally well-known behavior are discussed. Furthermore, the conditions for nonlinear temperature behavior are quantified and a concept is described which allows the determination of the temperature dependence of a single reaction pathway in a selection process.

Spirocyclic benzofurans (IV), (V) and (VII) as well as the corresponding benzopyrans are produced and tested as 1:1 mixtures of cis and trans diastereomers.

From insects to cancer: N-Cyano sulfoximines were evaluated for COX inhibition and antiproliferative activity against a panel of cancer cell lines. The most active compound exhibited potent COX-2 inhibition, some selectivity for COX-2 over COX-1, only slight cytotoxicity towards healthy cells (HaCaT skin cells), and no mutagenic potential (as determined by an Ames assay).

The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ(1) receptor (σ(1)R) antagonists are reported. The new compounds were evaluated in vitro in human σ(1)R and guinea pig σ(2) receptor (σ(2)R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores. A wide variety of amines and spacer lengths between the amino and pyrazole groups were tolerated, but only the ethylenoxy spacer and small cyclic amines provided compounds with sufficient selectivity for σ(1)R vs σ(2)R. The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862), which showed high activity in the mouse capsaicin model of neurogenic pain, emerged as the most interesting candidate. In addition, compound 28 exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound 28 to be selected as clinical candidate.

Sulfoximine-based acyclic triaryl olefins 8 and 9 have been prepared and initial studies have been performed to determine their biological profiles. In contrast to their sulfonyl-substituted analog 2 sulfoximines 8 and 9 show low COX inhibitory activity. All compounds affect the estrogen receptors. While sulfone 2 interacts exclusively with ER β, sulfoximines 8 and 9 reveal almost equal blocking potencies for both estrogen receptors, ER α and ER β. In the tested series, triaryl olefin 9a shows the highest inhibitory activities with 91% and 80%, respectively (at 10 μM).

Two series of σ(1) ligands with a spiro[[2]benzopyran-1,3'-pyrrolidine] (3) and a spiro[[2]benzofuran-1,3'-pyrrolidine] (4) framework were synthesized and pharmacologically evaluated. Several reaction steps were considerably improved by microwave irradiation. The σ(1) affinity of the spirocyclic ligands correlates nicely with the benzene-N-distance, i.e. 2341. The σ(1) affinity of both compound classes could be increased with large N-substituents (e.g. 2-phenylethyl, octyl). Nevertheless the benzyl derivative 4a represents the most promising σ(1) ligand (K(i) = 25 nM) due to its high selectivity against the σ(2) subtype (40-fold), the NMDA receptor and 5-HT(6) and 5-HT(7) receptors. Moreover, 4a did not inhibit the hERG channel in the heart.

The mechanism of the diastereoselection in the photosensitized[2 + 2]-cycloaddition reaction of ethylene to 5-alkoxy-2(5H)-furanones is investigated. The dependence of product ratio on the reaction temperature as well as on structural features of the enone system is measured. The structure dependent activation parameter differences (ΔΔH≠,ΔΔS≠) obtained by this method (modified Eyring plot) are used as a tool to characterize the stereoelectronic factors, which are responsible for the diastereoselection. In detail these factors involve: pyramidalization of the β-carbon, homoanomeric effect, and the steric requirements of the alkoxy substituent in the relaxed (3ππ*)-excited furanones.

Sulfoximines (VIII) and (X) are prepared by combining the original strategy for the synthesis of Vioxx® with the chemistry developed by the authors.