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BCL-XL, an antiapoptotic member of the BCL-2 family of proteins, drives tumor survival and maintenance and thus represents a key target for cancer treatment. Herein we report the rational design of a novel series of selective BCL-XL inhibitors exemplified by A-1293102. This molecule contains structural elements of selective BCL-XL inhibitor A-1155463 and the dual BCL-XL/BCL-2 inhibitors ABT-737 and navitoclax, while representing a distinct pharmacophore as assessed by an objective cheminformatic evaluation. A-1293102 exhibited picomolar binding affinity to BCL-XL and both efficiently and selectively killed BCL-XL-dependent tumor cells. X-ray crystallographic analysis demonstrated a key hydrogen bonding network in the P2 binding pocket of BCL-XL, while the bent-back moiety achieved efficient occupancy of the P4 pocket in a manner similar to that of navitoclax. A-1293102 represents one of the few distinct structural series of selective BCL-XL inhibitors, and thus serves as a useful tool for biological studies as well as a lead compound for further optimization.

Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-XL inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp3-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-XL. A-1331852 has since been used as a critical tool molecule for further exploring BCL-2 family protein biology, while also representing an attractive entry into a drug discovery program.

[Image: see text] BCL-X(L), an antiapoptotic member of the BCL-2 family of proteins, drives tumor survival and maintenance and thus represents a key target for cancer treatment. Herein we report the rational design of a novel series of selective BCL-X(L) inhibitors exemplified by A-1293102. This molecule contains structural elements of selective BCL-X(L) inhibitor A-1155463 and the dual BCL-X(L)/BCL-2 inhibitors ABT-737 and navitoclax, while representing a distinct pharmacophore as assessed by an objective cheminformatic evaluation. A-1293102 exhibited picomolar binding affinity to BCL-X(L) and both efficiently and selectively killed BCL-X(L)-dependent tumor cells. X-ray crystallographic analysis demonstrated a key hydrogen bonding network in the P2 binding pocket of BCL-X(L), while the bent-back moiety achieved efficient occupancy of the P4 pocket in a manner similar to that of navitoclax. A-1293102 represents one of the few distinct structural series of selective BCL-X(L) inhibitors, and thus serves as a useful tool for biological studies as well as a lead compound for further optimization.

A synthesis of a selective diacyl glycerolacyltransferase-1 (DGAT-1) inhibitor, 1, is described. The synthesis illustrates a diketone Favorskii reaction on 9 in place of the more common ketoester variant for generation of the dicarboxycyclopentane core, the development of an efficient classical resolution of a key cyclopentyl ketoacid intermediate 4, and an ambient temperature Suzuki−Miyaura coupling which avoids epimerization of the labile aryl ketone of 1.

Postprandial hypertriglyceridemia has been identified as a major independent risk factor for future cardiovascular events. Therefore, inhibition of triglyceride synthesis has enormous therapeutic potential in the treatment of metabolic disorders. Diacylglycerol acyltransferase (DGAT) enzymes catalyze the final and only committed step in triglyceride biosynthesis and have thus been identified as potential therapeutic targets to combat human cardio-metabolic diseases.Significant interest in DGAT-1 inhibitors has emerged in the last several years. To provide a perspective on the exciting features of this enzyme for targeting metabolic diseases, a summary of the biology and pharmacology surrounding the DGAT enzymes is presented. Following this is a discussion of the various chemotypes that have been disclosed within relevant patent applications published in 2008. Specifically, the similarities and differences of the chemical structures and the biological data that are provided to support the corresponding claims are presented.Small molecule and biologic-based DGAT inhibitors have been successfully used for the preclinical validation of DGAT enzymes as targets for the treatment of metabolic diseases. Given the advanced stage in which some of the chemical matter resides, it is expected that DGAT inhibitors will enter the clinic in the coming years.

The discovery of small molecule melanin concentrating hormone receptor (MHCr1) antagonists as novel therapeutic agents has been widely pursued across the pharmaceutical industry. While multiple chemotypes of small molecule MCHr1 antagonists have been identified and shown to induce weight loss in rodent models of obesity, many of these lead compounds have been found to cross react with the hERG channel. This review describes efforts that led to the identification of two sub-series of MCHr1 antagonists with low affinity for the hERG channel. Ultimately, however, the modifications introduced to thwart hERG channel activity resulted in lead compounds with sub-optimal CNS behavior.

We report the details of the first total synthesis of erythromycin B using two different strategies for the end game. The first of these follows a classical approach in which the desosamine and cladinose residues are sequentially appended to a macrocyclic lactone, which was formed by cyclization of a seco acid derivative, to give a bis-glycosylated macrolide intermediate that is converted into erythromycin B. The second strategy features an abiotic approach in which a seco acid bearing a desosamine residue is cyclized to give a monoglycosylated macrocyclic lactone that is then transformed into erythromycin B via a sequence of steps involving refunctionalizations and a glycosylation to introduce the cladinose moiety. Attempts to prepare a bis-glycosylated seco acid by de novo synthesis were unsuccessful. The syntheses of the key seco acid intermediates feature the oxidative transformation of a furan containing C(3)–C(10) to provide a dioxabicyclo[3.3.1]nonenone that served as a template on which to create the stereocenters at C(6) and C(8). A stereoselective aldol reaction was used to establish the C(11)–C(15) segment, and a stereoselective crotylation was implemented to introduce the propionate subunit comprising C(1)–C(2).

Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasma and brain. Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel.

An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor 1 (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (>40 microM) and brain (>20 microg/g) with

4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of cardiovascular safety revealed adverse hemodynamic effects at a plasma concentration comparable to the minimally effective therapeutic concentration. These results highlight the need for scrutiny of the cardiovascular safety profile of MCHr1 antagonists.

Optimization of a high-throughput screening hit against melanin-concentrating hormone receptor 1 (MCHr1) led to the discovery of 2-(4-benzyloxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide (7a). This compound was found to be a high-affinity ligand for MCHr1 and a potent inhibitor of MCH-mediated Ca(2+) release, showed good plasma and CNS exposure upon oral dosing in diet-induced obese mice, and is the first reported MCHr1 antagonist that is efficacious upon oral dosing in a chronic model of weight loss.

[12279-09-3] C32H56Cl2Rh2 (MW 717.50) InChI = 1S/4C8H14.2ClH.2Rh/c4*1-2-4-6-8-7-5-3-1;;;;/h4*1-2H,3-8H2;2*1H;;/q;;;;;;2*+1/p-2/b4*2-1-;;;; InChIKey = GQPAPAIPOLEZHT-XFCUKONHSA-L (convenient source of rhodium(I) and serves as an effective precatalyst in a variety of reactions including aryl- and vinyl-CH bond activation, hydroiminoacylation, cycloisomerization, and CC bond activation) Physical Data: mp 140 °C (dec). It exists as a reddish brown solid. Analysis of Reagent Purity: characteristic strong bands will appear at 1458, 1439, and 1350 cm−1 in the infrared spectrum. Preparative Methods: The reagent is prepared by adding an excess of cis-cyclooctene to an isopropanol–water (4:1) solution of rhodium(III) chloride 3-hydrate, filtering, and washing with ethanol.1 Handling, Storage, and Precautions: The catalyst should be handled under an inert atmosphere, such as dinitrogen or argon, and stored at reduced temperature (2–8 °C). The complex is susceptible to slow oxidation upon exposure to air, and appropriate precautions should be taken to maintain its catalytic efficacy.2 Standard good laboratory practices should be used when working with this reagent.

Two diastereomeric 4-methylene-2-cyclohexenones, otteliones A and B (1A and 1B), have been isolated from the freshwater plant Ottelia alismoides collected in the Nile Delta, Egypt. These natural products show remarkable in vitro cytotoxicity against various cancer cell lines. Ottelione B proved to have a constitution identical to that of the known (constitution only) ottelione A. The relative configurations of both 1A and 1B were studied by NOE and by the combination of molecular modeling and 1H NMR coupling constant analysis. A unique relative configurational assignment (1α,3β,3aβ,7aα) was deduced for 1B; 1A was assigned one of two alternative diastereomers (1α,3α,3aα,7aα or 1α,3α,3aβ,7aβ).

The synthesis of several chiral tropocoronands based on 1,2-cyclohexanediamine ( 7 ) and 1,2-diphenylethylenediamine ( 8 ) has been accomplished. X-ray crystallography has confirmed the structure of two metallated derivatives, Cu(II)(TC-4,cyhex) ( 9 ) and Ni(II)(TC-4,cyhex) ( 10 ), that are indicative of the types of chiral complexes that can be formed from these systems.

Several novel cascade processes have been designed and developed that involve sequential reactions of imines and iminium ions to form substituted quinolizidine ring systems in a single step from simple and readily available starting materials. The utility and promise of these cascade reactions is evident from their application to extraordinarily concise syntheses of the representative quinolizidine alkaloids (+/-)-epilupinine and (-)-epimyrtine.

A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.

The synthesis of several chiral tropocoronands based on 1,2-cyclohexanediamine ( 7 ) and 1,2-diphenylethylenediamine ( 8 ) has been accomplished. X-ray crystallography has confirmed the structure of two metallated derivatives, Cu(II)(TC-4,cyhex) ( 9 ) and Ni(II)(TC-4,cyhex) ( 10 ), that are indicative of the types of chiral complexes that can be formed from these systems.

Two diastereomeric 4-methylene-2-cyclohexenones, otteliones A and B (1A and 1B), have been isolated from the freshwater plant Ottelia alismoides collected in the Nile Delta, Egypt. These natural products show remarkable in vitro cytotoxicity against various cancer cell lines. Ottelione B proved to have a constitution identical to that of the known (constitution only) ottelione A. The relative configurations of both 1A and 1B were studied by NOE and by the combination of molecular modeling and 1H NMR coupling constant analysis. A unique relative configurational assignment (1α,3β,3aβ,7aα) was deduced for 1B; 1A was assigned one of two alternative diastereomers (1α,3α,3aα,7aα or 1α,3α,3aβ,7aβ).

Herein we report a concise protocol for the diastereoselective synthesis of novel bridged bicyclic lactams from commercially available components by the sequence of Ugi, ring-closing metathesis (RCM), and Heck reactions. X-ray diffraction studies revealed that the bicyclic products contain varying degrees of pyramidalization of the bridgehead nitrogen atom.

A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.

The discovery of small molecule melanin concentrating hormone receptor (MCHr1) antagonists as novel therapeutic agents for the treatment of obesity has been actively pursued across the pharmaceutical industry. While multiple chemotypes of small molecule MCHr1 antagonists have been identified and shown to deliver weight loss in animal models of obesity, many of these lead compounds have been found to cross-react with the hERG channel and/or demonstrate deleterious effects on cardiovascular hemodynamic parameters. This review describes an approach to rapidly identifying safer MCHr1 antagonists by placing assays to assess cardiovascular safety early in the lead optimization compound prioritization process. Ultimately, despite putting significant effort toward the discovery of a MCHr1 antagonist for the treatment of obesity, we were unable to deliver a candidate compound that attained an acceptable therapeutic index (TI = 30-100) in our in vivo models. Our inability to identify a compound with an acceptable therapeutic index was driven by two primary factors: 1) high levels of sustained drug exposure in the brain was required to achieve efficacy; and 2) many small molecule MCHR1 receptor antagonists suffer from receptor cross-reactivity that leads to cardiovascular toxicity at low multiples of their therapeutic plasma concentration.

[12092-47-6] C16H24Cl2Rh2 (MW 493.08) InChI = 1S/2C8H12.2ClH.2Rh/c2*1-2-4-6-8-7-5-3-1;;;;/h2*1-2,7-8H,3-6H2;2*1H;;/q;;;;2*+1/p-2/b2*2-1-,8-7-;;;; InChIKey = QSUDXYGZLAJAQU-MIXQCLKLSA-L (catalyst precursor for reactions involving heteroatom nucleophiles, aryl boronic acids, alkenes, alkynes, and a variety of organometallic reagents; most notably cross-couplings, asymmetric hydrogenations, Pauson–Khand annulations, carbonyl 1,2- and 1,4-additions, cycloisomerizations, and various tandem processes) Alternate Names: 1,5-cyclooctadienerhodium(I) chloride dimer and rhodium(I) chloride 1,5-cyclooctadiene complex dimer. Physical Data: mp 243 °C. It exists as hygroscopic yellow to orange crystals. Solubility: soluble in dichloromethane; moderately soluble in chloroform, acetic acid, and acetone; slightly soluble in ether, methanol, ethanol and benzene; insoluble in water. Analysis of Reagent Purity: strong infrared bands at 819, 964 and 998 cm−1 (Nujol mull). 1H NMR: 4.3 ppm and 2.6–1.7 ppm (CDCl3). Preparative Method: prepared by refluxing RhCl3·3H2O and excess cis,cis-1,5-cyclooctadiene in ethanol for 3–18 h. The solution is then cooled, the orange solid filtered, washed with ethanol and dried. Recrystallization from dichloromethane/diethyl ether or acetic acid gives orange prisms.1-3 Note that if the RhCl3·3H2O is particularly acidic, Na2CO3 can be added to the solution of rhodium complex in refluxing ethanol to obtain satisfactory results. Handling, Storage and Precautions: although the catalyst is quite air-stable, it should be handled under an inert atmosphere, and stored at reduced temperature (2–8 °C), to ensure optimal catalytic activity. The complex is susceptible to slow oxidation upon exposure to air, and appropriate precautions should be taken to maintain its catalytic efficacy. Reproducible results are best obtained when the catalyst is prepared fresh and used immediately. Standard good laboratory practices should be used when working with this reagent.

AMP-activated protein kinase (AMPK) is well established as a sensor and regulator of intracellular and whole-body energy metabolism. A high-throughput screen was performed in order to identify chemotypes that are bound by AMPK. A novel thienopyridone compound (1) was identified and subsequently optimized. The structure-activity relationships that emerged from this effort are described.

Publisher Summary The targeting of the lipid absorption and metabolism pathways has yielded several promising venues for the treatment of dyslipidemia and insulin resistance. Small molecule inhibitors of microsomal triglyceride-transfer protein (MTP) have conferred significant reductions in total and low density lipoprotein cholesterol and plasma triglyceride, in human subjects. Hormone sensitive lipase is still in the very early stages of drug development as a target, while efforts targeting enzymes involved with triglyceride and fatty acid synthesis are primarily in the pre-clinical stages. Results from genetically altered animals of diacylglyceride O-acyltransferase 1 (DGAT-1) and stearoyl-CoA desaturase 1 (SCD-1) provide significant impetus for the development of small molecule drugs. Effects on organs, such as skin and mammary glands will have to be considered going forward; however, the partial- or tissue-selective inhibition of these enzymes could yield novel and effective drugs with suitable therapeutic windows. Inhibition and activation of acetyl-CoA carboxylase and adenosine monophosphate-activated protein kinase, respectively, via small molecules represent intriguing possibilities to both mobilize fat oxidation as well as limit fatty acid synthesis. Because of the polyfactorial nature of disease states, such as obesity, type 2 diabetes, and Metabolic Syndrome, it is expected that drugs targeting the lipid synthesis and metabolism pathways will be used in the context of combination therapy.

Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats. Amide 25 is safe in a battery of in vitro and in vivo tests and may represent a new therapeutic agent for the treatment of type 2 diabetes.

The optimization of potent MCHr1 antagonist 1 with respect to improving its in vitro profile by replacement of the 3,4-methylenedioxy phenyl (piperonyl) moiety led to the discovery of 19, a compound that showed excellent MCHr1 binding and functional potencies in addition to possessing superior hERG separation, CYP3A4 profile, and receptor cross-reactivity profiles.

A series of potent 2-carboxychromone-based melanin-concentrating hormone receptor 1 (MCHr1) antagonists were synthesized and evaluated for hERG (human Ether-a-go-go Related Gene) channel affinity and functional blockade. Basic dialkylamine-terminated analogs were found to weakly bind the hERG channel and provided marked improvement in a functional patch-clamp assay versus previously reported antagonists of the series.

The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.

A series of urea-based N-1-(2-aminoethyl)-indazoles was synthesized and evaluated for melanin-concentrating hormone receptor 1 (MCHr1) antagonism in both binding and functional assays. Several compounds that acted as MCHr1 antagonists were identified, and optimization afforded a compound with excellent binding affinity, good functional potency, and oral efficacy in a chronic model for weight loss in diet-induced obese mice.