ABSTRACT
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
An indole-based P1 moiety was incorporated into a previously established factor Xa inhibitor series. The indole group was designed to hydrogen-bond with the carbonyl of Gly218, while its 3-methyl or 3-chloro substituent was intended to interact with Tyr228. These interactions were subsequently observed in the X-ray crystal structure of compound 18. SAR studies led to the identification of compound 20 as the most potent FXa inhibitor in this series (IC(50) = 2.4 nM, EC(2xPT) = 1.2 microM). An in-depth energetic analysis suggests that the increased binding energy of 3-chloroindole-versus 3-methylindole-containing compounds in this series is due primarily to (a) the more hydrophobic nature of chloro- versus methyl-containing compounds and (b) an increased interaction of 3-chloroindole versus 3-methylindole with Gly218 backbone. The stronger hydrophobicity of chloro- versus methyl-substituted aromatics may partly explain the general preference for chloro- versus methyl-substituted P1 groups in FXa, which extends beyond the current series.
Subject(s)
Drug Design , Enzyme Inhibitors , Factor Xa Inhibitors , Indoles , Quantum Theory , Animals , Binding Sites/drug effects , Computer Simulation , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Factor Xa/drug effects , Humans , Hydrogen Bonding , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Mice , Models, Chemical , Models, Molecular , Structure-Activity Relationship , Survival Analysis , Venoms/pharmacology , Venous Thrombosis/drug therapy , Venous Thrombosis/enzymologyABSTRACT
The synthesis and structure-activity relationships of novel dipeptidyl peptidase IV inhibitors replacing the classical cyanopyrrolidine P1 group with other small nitrogen heterocycles are described. A unique potency enhancement was achieved with beta-branched natural and unnatural amino acids, particularly adamantylglycines, linked to a (2S,3R)-2,3-methanopyrrolidine based scaffold.
Subject(s)
Dipeptides/chemistry , Dipeptidyl-Peptidase IV Inhibitors , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptides/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Drug Evaluation, Preclinical , Humans , Nitriles/chemistry , Nitriles/pharmacology , Structure-Activity RelationshipABSTRACT
The design and synthesis of a novel class of amino(methyl) pyrrolidine-based sulfonamides as potent and selective FXa inhibitors is reported. The amino(methyl) pyrrolidine scaffolds were designed based on the proposed bioisosterism to the piperazine core in known FXa inhibitors. The SAR study led to compound 15 as the most potent FXa inhibitor in this series, with an IC(50) of 5.5 nM and PT EC(2x) of 1.7 microM. The proposed binding models show that the pyrrolidine cores are in van der Waals contact with the enzyme surface, and the flexibility of amino(methyl) pyrrolidines allows the two nitrogen atoms to anchor both the P1 and P4 groups to fit similarly in the S1 and S4 pockets.
Subject(s)
Factor Xa Inhibitors , Pyrrolidines/chemistry , Serine Proteinase Inhibitors/pharmacology , Models, Molecular , Serine Proteinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
K(V)1.5 blockers have the potential to be atrium-selective agents for treatment of atrial fibrillation. The benzopyrans provide a template for the synthesis of potent and selective K(V)1.5 blockers.
Subject(s)
Atrial Fibrillation/drug therapy , Atrial Function/drug effects , Benzopyrans/pharmacology , Kv1.5 Potassium Channel/drug effects , Potassium Channel Blockers/pharmacology , Sulfonamides/pharmacology , Atrial Function/physiology , Benzopyrans/chemistry , Kv1.5 Potassium Channel/metabolism , Models, Chemical , Potassium Channel Blockers/chemical synthesis , Sulfonamides/chemistryABSTRACT
A series of potent inhibitors of the sodium hydrogen exchanger-1 (NHE-1) is described. Structure-activity relationships identified the 3-methyl-4-fluoro analog 9t as a highly potent (IC50 = 0.0065 microM) and selective (NHE-2/NHE-1=1400) non-acylguanidine NHE-1 inhibitor. Pharmacokinetic studies showed that compound 9t has an oral bioavailability of 52% and a plasma half life of 1.5 h in rats. Because of its promising potency, selectivity, and a good pharmacokinetic profile, compound 9t was selected for further studies.
Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Inhibitory Concentration 50 , Molecular Structure , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Sodium-Hydrogen Exchangers/metabolism , Structure-Activity RelationshipABSTRACT
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
A series of inhibitors of mammalian 15-lipoxygenase based on tryptamine and homotryptamine scaffolds is described. Compounds with aryl substituents at C-2 of the indole core of tryptamine and homotryptamine sulfonamides (e.g., 37a-p) proved to be potent inhibitors of the isolated enzyme. Selected compounds also demonstrated desirable inhibition selectivities over isozymes 5- and P-12-LO.
Subject(s)
Enzyme Inhibitors/pharmacology , Lipoxygenase Inhibitors , Sulfonamides/pharmacology , Tryptamines/chemistry , Animals , Enzyme Inhibitors/chemistry , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
Mitochondrial F(1)F(0)-ATPase normally synthesizes ATP in the heart, but under ischemic conditions this enzyme paradoxically causes ATP hydrolysis. Nonselective inhibitors of this enzyme (aurovertin, oligomycin) inhibit ATP synthesis in normal tissue but also inhibit ATP hydrolysis in ischemic myocardium. We characterized the profile of aurovertin and oligomycin in ischemic and nonischemic rat myocardium and compared this with the profile of BMS-199264, which only inhibits F(1)F(0)-ATP hydrolase activity. In isolated rat hearts, aurovertin (1-10 microM) and oligomycin (10 microM), at concentrations inhibiting ATPase activity, reduced ATP concentration and contractile function in the nonischemic heart but significantly reduced the rate of ATP depletion during ischemia. They also inhibited recovery of reperfusion ATP and contractile function, consistent with nonselective F(1)F(0)-ATPase inhibitory activity, which suggests that upon reperfusion, the hydrolase activity switches back to ATP synthesis. BMS-199264 inhibits F(1)F(0) hydrolase activity in submitochondrial particles with no effect on ATP synthase activity. BMS-199264 (1-10 microM) conserved ATP in rat hearts during ischemia while having no effect on preischemic contractile function or ATP concentration. Reperfusion ATP levels were replenished faster and necrosis was reduced by BMS-199264. ATP hydrolase activity ex vivo was selectively inhibited by BMS-199264. Therefore, excessive ATP hydrolysis by F(1)F(0)-ATPase contributes to the decline in cardiac energy reserve during ischemia and selective inhibition of ATP hydrolase activity can protect ischemic myocardium.
Subject(s)
Adenosine Triphosphate/metabolism , Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Myocardial Ischemia/metabolism , Proton-Translocating ATPases/metabolism , Animals , Aurovertins/chemistry , Aurovertins/pharmacology , Cell Survival/physiology , Hydrolysis , Imidazoles/chemistry , Male , Mitochondria/enzymology , Myocardium/cytology , Myocardium/metabolism , Oligomycins/chemistry , Oligomycins/pharmacology , Proton-Translocating ATPases/antagonists & inhibitors , Rats , Rats, Sprague-Dawley , Uncoupling Agents/chemistry , Uncoupling Agents/pharmacologyABSTRACT
A series of benzodiazepine-based inhibitors of mitochondrial F(1)F(0) ATP hydrolase were prepared and evaluated for their ability to selectively inhibit the enzyme in the forward direction. Compounds from this series showed excellent potency and selectivity for ATP hydrolase versus ATP synthase, suggesting a potentially beneficial profile useful for the treatment of ischemic heart disease.
Subject(s)
Adenosine Triphosphate/metabolism , Benzodiazepines/pharmacology , Enzyme Inhibitors/pharmacology , Mitochondria/enzymology , Mitochondrial Proton-Translocating ATPases/antagonists & inhibitors , Animals , Benzodiazepines/chemical synthesis , Cattle , Enzyme Inhibitors/chemical synthesis , Mitochondrial Proton-Translocating ATPases/metabolism , Structure-Activity RelationshipABSTRACT
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
In this paper we show that 4-aryl-CH2-imidazole-substituted benzopyran compounds with 3S,4R-stereochemistry are cardioprotective by inhibiting the F1F0 mitochondrial ATP hydrolase. Compounds (e.g., 13) with 3R,4S-stereochemistry act as mitochondrial KATP openers. This resulted from an inversion of stereochemistry for the F1F0 mitochondrial ATP hydrolase vs mitochondrial KATP. Structure-activity relationships for the inhibition of mitochondrial ATP hydrolase are also delineated. It is not clear how 13 (3R,4S) can selectively inhibit the hydrolytic activity of the F1F0 mitochondrial enzyme without interfering with the synthase activity.
Subject(s)
Benzopyrans/chemical synthesis , Cardiotonic Agents/chemical synthesis , Imidazoles/chemical synthesis , Mitochondrial Proton-Translocating ATPases/antagonists & inhibitors , Adenosine Triphosphate/biosynthesis , Adenosine Triphosphate/metabolism , Animals , Benzopyrans/chemistry , Benzopyrans/pharmacology , Cardiotonic Agents/chemistry , Cardiotonic Agents/pharmacology , Cattle , Citrate (si)-Synthase/metabolism , Electron Transport Complex IV/metabolism , Hydrolysis , Imidazoles/chemistry , Imidazoles/pharmacology , In Vitro Techniques , Myocardial Contraction/drug effects , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
N,N'-Disubstituted ketene aminals are bioisosteres of thioureas and are useful building blocks in many synthetic operations. A convenient one-pot synthesis of N,N'-disubstituted ketene aminals from activated methylene compounds and isothiocyanates is described. Most of these aminals exist in rotameric equilibrium around the central C=C bonds in solution, and the rotamers are stabilized by intramolecular hydrogen bonding both in solution and in solid states.
ABSTRACT
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
Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability.
Subject(s)
Cation Transport Proteins/antagonists & inhibitors , Guanidines/administration & dosage , Imidazoles/administration & dosage , Membrane Proteins/antagonists & inhibitors , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Administration, Oral , Biological Availability , Cation Transport Proteins/metabolism , Cell Line , Guanidines/chemistry , Guanidines/pharmacokinetics , Humans , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Membrane Proteins/metabolism , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Sodium-Hydrogen Exchanger 1 , Sodium-Hydrogen Exchangers/metabolism , StereoisomerismABSTRACT
ATP-sensitive potassium channel (K(ATP)) openers as a class protect ischemic myocardium. The protective effects are independent of vasodilator activity and effects on action potential shortening, actions typically associated with sarcolemmal K(ATP) activation. BMS-191095 is a novel mitochondrial K(ATP) opener which protects ischemic myocardium while having no electrophysiologic or vasodilator effects (determined in vitro and in vivo). The cardioprotective effects were determined in isolated rat hearts subjected to ischemia and reperfusion. Protective effects were deduced from increased time to contracture formation during ischemia, improved reperfusion recovery of contractile function, and reduced reperfusion LDH release. The cardioprotective effects of BMS-191095 were observed at concentrations at which this compound selectively opened cardiac mitochondrial K(ATP) channels. This effect was consistent with the pharmacologic profile of this agent. The protective effects were abolished by mitochondrial K(ATP) inhibition. Unlike first-generation K(ATP) openers, BMS-191095 is expected to protect ischemic myocardium with little hemodynamic sequelae and without any proarrhythmic potential. BMS-191095 is potentially useful clinically as a cardioprotective agent. It is also a useful tool for basic research.