Development of a Convergent Large-Scale Synthesis for Venetoclax, a First-in-Class BCL-2 Selective Inhibitor.

The process development of a new synthetic route leading to an efficient and robust synthetic process for venetoclax (1: the active pharmaceutical ingredient (API) in Venclexta) is described. The redesigned synthesis features a Buchwald-Hartwig amination to construct the core ester 23c in a convergent fashion by connecting two key building blocks (4c and 26), which is then followed by a uniquely effective saponification reaction of 23c using anhydrous hydroxide generated in situ to obtain 2. Finally, the coupling of the penultimate core acid 2 with sulfonamide 3 furnishes drug substance 1 with consistently high quality. The challenges and solutions for the key Pd-catalyzed C-N cross-coupling will also be discussed in detail. The improved synthesis overcomes many of the initial scale-up challenges and was accomplished in 46% overall yield from 3,3-dimethyldicyclohexanone (6), more than doubling the overall yield of the first generation route. The new process was successfully implemented for producing large quantities of 1 with >99% area purity.

Improved synthesis of 3-substituted-4-amino-[3,2-c]-thienopyridines.

Two syntheses of 3-substituted-4-amino-[3,2-c]thienopyridines have been developed to replace the standard literature route to these compounds, which uses unattractive conditions involving azide and high temperatures. The first synthesis utilizes a Friedel-Crafts reaction as its key ring-forming step, whereas the second route relies on an unprecedented intramolecular reductive cyclization between a nitroolefin and a nitrile as its key ring-forming step. The development and optimization of each 3-substituted-4-amino-[3,2-c]thienopyridine synthesis is discussed and a comparison of the routes is presented.

Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor.

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.

Discovery of ((4R,5S)-5-amino-4-(2,4,5- trifluorophenyl)cyclohex-1-enyl)-(3- (trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (ABT-341), a highly potent, selective, orally efficacious, and safe dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

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.

Screening for cardiovascular safety: a structure-activity approach for guiding lead selection of melanin concentrating hormone receptor 1 antagonists.

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 <15% change in cardiovascular endpoints. As a result of these stringent requirements, lead optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHr1 antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.

Optimization of chromone-2-carboxamide melanin concentrating hormone receptor 1 antagonists: assessment of potency, efficacy, and cardiovascular safety.

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.

Identification of 2-(4-benzyloxyphenyl)-N- [1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide, an orally efficacious melanin-concentrating hormone receptor 1 antagonist for the treatment of obesity.

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.

Discovery and characterization of aminopiperidinecoumarin melanin concentrating hormone receptor 1 antagonists.

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.

An evaluation of 3,4-methylenedioxy phenyl replacements in the aminopiperidine chromone class of MCHr1 antagonists.

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.

Identification of diamino chromone-2-carboxamides as MCHr1 antagonists with minimal hERG channel activity.

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.

Constrained 7-fluorocarboxychromone-4-aminopiperidine based Melanin-concentrating hormone receptor 1 antagonists: the effects of chirality on substituted indan-1-ylamines.

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.

Aminopiperidine indazoles as orally efficacious melanin concentrating hormone receptor-1 antagonists.

The synthesis and biological evaluation of novel 3-amino indazole melanin concentrating hormone receptor-1 antagonists are reported, several of which demonstrated functional activity of less than 100nM. Compounds 19 and 28, two of the more potent compounds identified in this study, were characterized by high exposure in the brain and demonstrated robust efficacy when dosed in diet-induced obese mice.

Synthesis and evaluation of urea-based indazoles as melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity.

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.