ABSTRACT
The potent MCHR1 in vitro and in vivo antagonist activity of a series of cyclic tertiary alcohols derived from compound 2b is described. Subsequent pharmacokinetic and pharmacodynamic studies identified BMS-814580 (compound 10) as a highly efficacious antiobesity agent with a relatively clean in vitro and in vivo safety profile.
Subject(s)
Anti-Obesity Agents/chemistry , Anti-Obesity Agents/therapeutic use , Obesity/drug therapy , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Receptors, Somatostatin/antagonists & inhibitors , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Dogs , Halogenation , Humans , Macaca fascicularis , Male , Mice , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Receptors, Somatostatin/metabolism , Structure-Activity RelationshipABSTRACT
In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.
Subject(s)
Carboxylic Acids/chemistry , Drug Discovery , Factor VIIa/antagonists & inhibitors , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Benzamidines , Crystallography, X-Ray , Dose-Response Relationship, Drug , Factor VIIa/metabolism , Humans , Models, Molecular , Molecular Structure , Serine Proteinase Inhibitors/chemical synthesis , Structure-Activity RelationshipABSTRACT
The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT2C is a well validated target for anti-obesity therapy. The synthesis and structure-activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists are presented. Several members of this series were identified as potent 5-HT2C receptor agonists with high functional selectivity against the 5-HT2A and 5-HT2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.
Subject(s)
Isoquinolines/pharmacology , Pyrazines/pharmacology , Receptor, Serotonin, 5-HT2C/metabolism , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Eating/drug effects , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Models, Molecular , Molecular Structure , Pyrazines/chemical synthesis , Pyrazines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide-valerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC(50) of 7 nM and EC(2×PT) of 1.7 µM. The X-ray structure of compound 40 bound to FXa shows that the sulfonamide-valerolactam scaffold anchors the aryl group in the S1 and the novel acylcytisine pharmacophore in the S4 pockets.
Subject(s)
Anticoagulants/chemistry , Factor Xa Inhibitors , Piperidones/chemistry , Serine Proteinase Inhibitors/chemistry , Anticoagulants/chemical synthesis , Anticoagulants/pharmacology , Binding Sites , Crystallography, X-Ray , Enzyme Activation/drug effects , Factor Xa/metabolism , Humans , Lactams/chemistry , Molecular Conformation , Piperidones/chemical synthesis , Piperidones/pharmacology , Protein Structure, Tertiary , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4 nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity (IC(50)=0.3 microM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC(50)=9 nM, EC(2xPT)=2.5 microM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.
Subject(s)
Anticoagulants/chemistry , Factor Xa Inhibitors , Guanidines/chemistry , Serine Proteinase Inhibitors/chemistry , Anticoagulants/pharmacology , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP3A Inhibitors , Drug Discovery , Guanidines/pharmacology , Humans , Inhibitory Concentration 50 , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
The N,N'-disubstituted cyanoguanidine is an excellent bioisostere of the thiourea and ketene aminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, K(i)=6.5nM, EC(2xPT)=32muM) as a selective, orally bioavailable FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. The X-ray crystal structure of 4 bound in FXa is presented and key ligand-protein interactions are discussed.
Subject(s)
Antithrombin III/pharmacology , Benzofurans/pharmacology , Guanidines/chemistry , Lactams/chemistry , Administration, Oral , Animals , Antithrombin III/chemistry , Benzofurans/chemistry , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Dogs , Haplorhini , Humans , Inhibitory Concentration 50 , Kinetics , Lactams/pharmacology , Ligands , Models, Chemical , Rats , Structure-Activity Relationship , Thiourea/chemistryABSTRACT
3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.
Subject(s)
Hydroxymethylglutaryl CoA Reductases/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Triazoles/chemical synthesis , Administration, Oral , Animals , Biological Availability , Chemical and Drug Induced Liver Injury/etiology , Cholesterol/biosynthesis , Cholesterol/blood , Crystallography, X-Ray , Dogs , Female , Guinea Pigs , Haplorhini , Humans , Hydroxymethylglutaryl CoA Reductases/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/toxicity , In Vitro Techniques , Liver/drug effects , Liver/metabolism , Models, Molecular , Muscle Cells/cytology , Muscle Cells/drug effects , Muscle Cells/metabolism , Pyrimidines/pharmacology , Pyrimidines/toxicity , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Triazoles/pharmacology , Triazoles/toxicityABSTRACT
N,N'-Disubstituted ketene aminals are good bioisosteres of thiourea functional groups. We report the design and synthesis of a novel class of ketene aminal-based lactam derivatives as potent and orally active FXa inhibitors.
Subject(s)
Ethylenes/pharmacology , Factor Xa Inhibitors , Ketones/pharmacology , Lactams/pharmacology , Administration, Oral , Ethylenes/administration & dosage , Ethylenes/chemistry , Humans , Ketones/administration & dosage , Ketones/chemistry , Lactams/administration & dosage , Models, Molecular , Molecular Conformation , Structure-Activity RelationshipABSTRACT
The preferred absolute configuration of two series of F(1)F(0)-ATP synthase inhibitors was determined. Although the configuration of the active enantiomer in each series is different, each series presents the same 'triaryl' pharmacophore to the enzyme binding site.
Subject(s)
Mitochondria/enzymology , Proton-Translocating ATPases/metabolism , Binding Sites , Models, Molecular , StereoisomerismABSTRACT
A series of substituted guanidine derivatives were prepared and evaluated as potent and selective inhibitors of mitochondrial F(1)F(0) ATP hydrolase. The initial thiourethane derived lead molecules possessed intriguing in vitro pharmacological profiles, though contained moieties considered non-drug-like. Analogue synthesis efforts led to compounds with maintained potency and superior physical properties. Small molecules in this series which potently and selectivity inhibit ATP hydrolase and not ATP synthase may have utility as cardioprotective agents.
Subject(s)
Adenosine Triphosphate/metabolism , Enzyme Inhibitors/pharmacology , Guanidines/pharmacology , Mitochondria/enzymology , Mitochondrial Proton-Translocating ATPases/antagonists & inhibitors , Animals , Cattle , Enzyme Inhibitors/chemical synthesis , Guanidines/chemical synthesis , Mitochondrial Proton-Translocating ATPases/metabolism , Structure-Activity RelationshipABSTRACT
Class III anti-arrhythmic drugs (e.g., dofetilide) prolong cardiac action potential duration (APD) by blocking the fast component of the delayed rectifier potassium current (I(Kr)). The block of I(Kr) can result in life threatening ventricular arrhythmias (i.e., torsades de pointes). Unlike I(Kr), the role of the slow component of the delayed rectifier potassium current (I(Ks)) becomes significant only at faster heart rate. Therefore selective blockers of I(Ks) could prolong APD with a reduced propensity to cause pro-arrhythmic side effects. This report describes structure-activity relationships (SARs) of a series of I(Ks) inhibitors derived from 6-alkoxytetralones with good in vitro activity (IC(50) > or =30 nM) and up to 40-fold I(Ks)/I(Kr) selectivity.
Subject(s)
Amino Alcohols/pharmacology , Potassium Channel Blockers/pharmacology , Potassium Channels, Voltage-Gated , Potassium Channels/physiology , Tetrahydronaphthalenes/pharmacology , Amino Alcohols/chemistry , Animals , Delayed Rectifier Potassium Channels , Guinea Pigs , Ketones/chemistry , Ketones/pharmacology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/physiology , Potassium Channel Blockers/chemistry , Tetrahydronaphthalenes/chemistryABSTRACT
A number of 4'-heterocyclic biphenylsulfonamide derivatives, formally derived from BMS-193884 (1) by replacing the oxazole ring with other heterocyclic rings, are potent and selective endothelin A (ET(A)) receptor antagonists. Among the analogues examined, the pyrimidine derivative 18 is the most potent (K(i)=0.9 nM) and selective for the ET(A) receptor, approximately equivalent to 1.