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
In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.
Subject(s)
Benzofurans/pharmacology , Fibrinolytic Agents/pharmacology , Hemorrhage/prevention & control , Receptors, Thrombin/antagonists & inhibitors , Thrombosis/prevention & control , Animals , Benzofurans/chemistry , Benzofurans/pharmacokinetics , Biological Availability , Disease Models, Animal , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacokinetics , HEK293 Cells , Hemorrhage/metabolism , Humans , Macaca fascicularis , Models, Chemical , Molecular Structure , Platelet Aggregation/drug effects , Receptors, Thrombin/genetics , Receptors, Thrombin/metabolism , Structure-Activity Relationship , Thrombosis/metabolismABSTRACT
Polo-like kinase 1 (Plk1) plays several roles in cell division and it is a recognized cancer drug target. Plk1 levels are elevated in cancer and several types of cancer cells are hypersensitive to Plk1 inhibition. Small molecule inhibitors of the kinase domain (KD) of Plk1 have been developed. Their selectivity is limited, which likely contributes to their toxicity. Polo-like kinases are characterized by a Polo-Box Domain (PBD), which mediates interactions with phosphorylation substrates or regulators. Inhibition of the PBD could allow better selectivity or result in different effects than inhibition of the KD. In vitro screens have been used to identify PBD inhibitors with mixed results. We developed the first cell-based assay to screen for PBD inhibitors, using Bioluminescence Resonance Energy Transfer (BRET). We screened through 112 983 compounds and characterized hits in secondary biochemical and biological assays. Subsequent Structure-Activity Relationship (SAR) analysis on our most promising hit revealed that it requires an alkylating function for its activity. In addition, we show that the previously reported PBD inhibitors thymoquinone and Poloxin are also alkylating agents. Our cell-based assay is a promising tool for the identification of new PBD inhibitors with more drug-like profiles using larger and more diverse chemical libraries.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Alkylating Agents/chemistry , Alkylating Agents/pharmacology , Benzoates/chemistry , Benzoates/pharmacology , Benzoquinones/chemistry , Benzoquinones/pharmacology , Bioluminescence Resonance Energy Transfer Techniques , HEK293 Cells , High-Throughput Screening Assays , Humans , Protein Interaction Domains and Motifs , Protein Kinase Inhibitors/chemistry , Quinones/chemistry , Quinones/pharmacology , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Structure-Activity Relationship , Polo-Like Kinase 1ABSTRACT
A series of lysine sulfonamide analogues bearing Nepsilon-acyl aromatic amino acids were synthesized using an efficient synthetic route. Evaluation of these novel protease inhibitors revealed compounds with high potency against wild-type and multiple-protease inhibitor-resistant HIV viruses.
Subject(s)
Amino Acids/chemistry , Anti-HIV Agents/pharmacology , HIV Protease Inhibitors/pharmacology , Lysine/chemistry , Sulfonamides/pharmacology , Acylation , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Cell Line , Drug Design , Drug Evaluation, Preclinical , HIV/drug effects , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/chemistry , Humans , In Vitro Techniques , Lysine/analogs & derivatives , Microbial Sensitivity Tests , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistryABSTRACT
Several novel racemic aminotetralin derivatives have been prepared using a stereoselective aziridine ring opening reactions and were evaluated for their micro-opioid receptor binding affinity. Selectivity index towards other opioid receptors and antinociceptive activity in mice have been evaluated for the most potent derivatives.
Subject(s)
Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/pharmacology , Receptors, Opioid, mu/drug effects , Tetrahydronaphthalenes/chemical synthesis , Tetrahydronaphthalenes/pharmacology , Animals , Indicators and Reagents , Mice , Pain Measurement/drug effects , Receptors, Opioid, delta/drug effects , Receptors, Opioid, delta/metabolism , Receptors, Opioid, kappa/drug effects , Receptors, Opioid, kappa/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Cryptophycin A, a cyclic depsipeptide isolated from the blue-green alga (cyanobacterium) Nostocsp.GSV 224, has shown excellent activity against solid tumors implanted in mice. The benzylic epoxide, which was shown to be very important for biological activity, is also fairly unstable under both acidic and alkaline conditions. The high doses needed to observe in vivo activity might be a result of this instability. In order to solve this problem while preserving the electrophilic character of the benzylic position, enones 1 and 2 have been proposed as promising analogs of the natural product, and a convergent total synthesis of these compounds is described. In addition, the same strategy was used to prepare Cryptophycins A, B, C, and D.
