ABSTRACT
The synthesis of a novel class of piperazine benzamide (reverse amides) targeting the human ß3-adrenergic receptor for the treatment of overactive bladder (OAB) is described. The SAR studies directed towards maintaining well established ß3 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.
Subject(s)
Adrenergic beta-3 Receptor Agonists/pharmacology , Piperazines/pharmacology , Urinary Bladder, Overactive/drug therapy , Adrenergic beta-3 Receptor Agonists/chemistry , Adrenergic beta-3 Receptor Agonists/therapeutic use , Humans , Piperazines/chemistry , Piperazines/therapeutic use , Structure-Activity RelationshipABSTRACT
The discovery of vibegron, a potent and selective human ß3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical ß3-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 ß3-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.
Subject(s)
Adrenergic beta-3 Receptor Agonists/therapeutic use , Pyrimidinones/therapeutic use , Pyrrolidines/therapeutic use , Urinary Bladder, Overactive/drug therapy , Adrenergic beta-3 Receptor Agonists/pharmacokinetics , Adrenergic beta-3 Receptor Agonists/toxicity , Animals , CHO Cells , Cricetinae , Cricetulus , Drug Discovery , Female , Humans , Lipidoses/chemically induced , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Models, Molecular , Pyrimidinones/pharmacokinetics , Pyrimidinones/toxicity , Pyrrolidines/pharmacokinetics , Pyrrolidines/toxicity , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, beta/drug effects , Receptors, Adrenergic, beta/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Structure-Activity Relationship , Urinary Bladder/drug effects , Urination/drug effects , X-Ray DiffractionABSTRACT
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 9 µM to 0.016 µM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2 µM to 0.09 µM. 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.
Subject(s)
Anticoagulants/chemistry , Anticoagulants/pharmacology , Factor IXa/antagonists & inhibitors , Binding Sites , Drug Discovery , Humans , Models, Molecular , Molecular Structure , Protein ConformationABSTRACT
A series of conformationally restricted acetanilides were synthesized and evaluated as ß3-adrenergic receptor agonists (ß3-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 ß3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent ß3-AR mediated responses in a rat bladder hyperactivity model.
Subject(s)
Acetanilides/chemical synthesis , Acetanilides/pharmacology , Adrenergic beta-3 Receptor Agonists/chemical synthesis , Adrenergic beta-3 Receptor Agonists/pharmacology , Urinary Bladder, Overactive/drug therapy , Acetanilides/therapeutic use , Adrenergic beta-3 Receptor Agonists/therapeutic use , Animals , CHO Cells , Cricetinae , Cricetulus , Drug Design , Humans , Magnetic Resonance Spectroscopy , Molecular ConformationABSTRACT
A series of amide derived beta(3)-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from 1, is used to lay the SAR foundation for second generation beta(3)-AR agonists for the treatment of overactive bladder.
Subject(s)
Acetamides/pharmacology , Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Antagonists/pharmacology , Benzamides/pharmacology , Acetamides/pharmacokinetics , Adrenergic beta-Antagonists/pharmacokinetics , Animals , Benzamides/pharmacokinetics , Rodentia , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Anti-Obesity Agents/pharmacology , Benzodiazepines/pharmacology , Indoles/pharmacology , Obesity/drug therapy , Receptor, Cholecystokinin A/agonists , Thiazoles/pharmacology , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/chemistry , Benzodiazepines/chemical synthesis , Benzodiazepines/chemistry , Chemokines, CC , Humans , Indoles/chemical synthesis , Indoles/chemistry , Methylamines/chemical synthesis , Methylamines/chemistry , Methylamines/pharmacology , Mice , Piperazine , Piperazines/chemistry , Receptors, Cholecystokinin/agonists , Receptors, Cholecystokinin/chemistry , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
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.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Piperidines/chemistry , Piperidines/pharmacology , Animals , Area Under Curve , Biological Availability , Half-Life , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Molecular Structure , Piperidines/blood , Rats , Structure-Activity RelationshipABSTRACT
A series of beta-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-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC(50) = 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.