ABSTRACT
Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (43), and a backup clinical candidate, BMS-986141 (49). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.
Subject(s)
Platelet Aggregation , Thrombosis , Benzofurans , Blood Platelets , Humans , Imidazoles , Morpholines , Receptor, PAR-1 , Receptors, Thrombin , Thiazoles , Thrombin , Thrombosis/drug therapyABSTRACT
The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.
Subject(s)
Anti-HIV Agents/pharmacology , Drug Discovery , Drug Resistance, Viral/drug effects , HIV-1/drug effects , Pyridones/chemistry , Pyridones/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Cells, Cultured , Crystallography, X-Ray , Dogs , HIV-1/genetics , Humans , Inhibitory Concentration 50 , Molecular Structure , Mutation , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Inhibitors/chemistryABSTRACT
Weak protein interactions between ubiquitin and the ubiquitin-proteasome system (UPS) enzymes that mediate its covalent attachment to substrates serve to position ubiquitin for optimal catalytic transfer. We show that a small-molecule inhibitor of the E2 ubiquitin-conjugating enzyme Cdc34A, called CC0651, acts by trapping a weak interaction between ubiquitin and the E2 donor ubiquitin-binding site. A structure of the ternary CC0651-Cdc34A-ubiquitin complex reveals that the inhibitor engages a composite binding pocket formed from Cdc34A and ubiquitin. CC0651 also suppresses the spontaneous hydrolysis rate of the Cdc34A-ubiquitin thioester without decreasing the interaction between Cdc34A and the RING domain subunit of the E3 enzyme. Stabilization of the numerous other weak interactions between ubiquitin and UPS enzymes by small molecules may be a feasible strategy to selectively inhibit different UPS activities.
Subject(s)
Amino Acids/chemistry , Biphenyl Compounds/chemistry , Ubiquitin-Conjugating Enzymes/antagonists & inhibitors , Ubiquitin/chemistry , Amino Acids/pharmacology , Binding Sites , Biphenyl Compounds/pharmacology , Coordination Complexes/chemistry , Crystallography, X-Ray , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Models, Molecular , Protein Binding , Protein Stability/drug effects , Small Molecule Libraries/pharmacologyABSTRACT
Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. Previous reports have demonstrated that the diketoacid-based chemotype is a useful starting point for the design of inhibitors of this enzyme. In this study, one of the ketone groups is replaced by a benzylamide resulting in a new potent chemotype. A preliminary SAR study is carried out to investigate the substitution requirements on the phenyl ring and methylene group of the benzylamide.
Subject(s)
Amides/chemistry , Anti-HIV Agents/pharmacology , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase/chemistry , Keto Acids/chemistry , Anti-HIV Agents/chemistry , Drug Design , Electrons , Enzyme Inhibitors/pharmacology , HIV Integrase Inhibitors/chemistry , Inhibitory Concentration 50 , Integrases/chemistry , Models, Chemical , Molecular Structure , Nitrogen/chemistry , Structure-Activity RelationshipABSTRACT
Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. A previous study of the diketoacid-based chemotype suggested that there are two aryl-binding domains on integrase. In this study, modifications to the indole-based diketoacid chemotype are explored. It is demonstrated that the indole group can be replaced with secondary but not tertiary (e.g., N-methyl) aniline-based amides without sacrificing in vitro inhibitory activity. The difference in activity between the secondary and tertiary amides is most likely due to the opposite conformational preferences of the amide bonds, s-trans for the secondary-amide and s-cis for the tertiary-amide. However, it was found that the conformational preference of the tertiary amide can be reversed by incorporating the amide nitrogen atom into an indoline heterocycle, resulting in very potent integrase inhibitors.