The discovery of vibegron, a potent and selective human β3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical β3-AR agonist MK-0634 (3) exhibited ...efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived β3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure–activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.
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The synthesis of a novel class of piperazine benzamide (reverse amides) targeting the human β3-adrenergic receptor for the treatment of overactive bladder (OAB) is described. The SAR ...studies directed towards maintaining well established β3 potency and selectivities while improving the overall pharmacokinetic profile in the reverse amide class will be evaluated. The results and consequences associated with functional activity at the norepinephrine transporter (NET) will also be discussed.
The synthesis of a novel class of piperazine benzamide (reverse amides) targeting the human β
-adrenergic receptor for the treatment of overactive bladder (OAB) is described. The SAR studies directed ...towards maintaining well established β
potency and selectivities while improving the overall pharmacokinetic profile in the reverse amide class will be evaluated. The results and consequences associated with functional activity at the norepinephrine transporter (NET) will also be discussed.
A series of conformationally restricted acetanilides were synthesized and evaluated as β3-adrenergic receptor agonists (β3-AR) for the treatment of overactive bladder (OAB). Optimization studies ...identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine β3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent β3-AR mediated responses in a rat bladder hyperactivity model.
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Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a 6-5-heteroaryl via an alkyl amine. In the case where ...this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9μM to 0.016μM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2μM to 0.09μM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts.
A series of β-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the ...metabolic profile of early analogues led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-1,2,4triazolo1,5-apyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC50 = 6.3 nM) with excellent selectivity, oral bioavailability in preclinical species, and in vivo efficacy in animal models. Compound 6 was selected for further characterization as a potential new treatment for type 2 diabetes.
The synthesis and biological profile of imidazole carboxamides of general structure 6 as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described.
The discovery and ...structure–activity relationship of 1,2-diarylimidazole piperazine carboxamides bearing polar side chains as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. Optimization of this series resulted in the discovery of isopropyl carboxamide 40, a CCK1R agonist with sub-nanomolar functional and binding activity as well as excellent potency in a mouse overnight food intake reduction assay.
Substituted 3-aminopiperidines 3 were evaluated as DPP-4 inhibitors. The inhibitors showed good DPP-4 potency with superb selectivity over other peptidases (QPP, DPP8, and DPP9). Selected DPP-4 ...inhibitors were further evaluated for their hERG potassium channel, L-type calcium channel, Cyp2D6, and pharmacokinetic profiles.
Substituted 3-aminopiperidines 3 were evaluated as DPP-4 inhibitors. The inhibitors showed good DPP-4 potency with superb selectivity over other peptidases (QPP, DPP8, and DPP9). Selected DPP-4 inhibitors were further evaluated for their hERG potassium channel, calcium channel, Cyp2D6, and pharmacokinetic profiles.
