A5030883249- Blood Coagulation and Thrombosis Mechanisms
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Atrial Fibrillation Management and Outcomes
- Vitamin K Research Studies
- Protease and Inhibitor Mechanisms
- Synthesis and Catalytic Reactions
- Chemical Synthesis and Analysis
- Renin-Angiotensin System Studies
- Antiplatelet Therapy and Cardiovascular Diseases
- Receptor Mechanisms and Signaling
- Organic Chemistry Cycloaddition Reactions
- Venous Thromboembolism Diagnosis and Management
- Peptidase Inhibition and Analysis
- Protein Kinase Regulation and GTPase Signaling
- Enzyme function and inhibition
- Hemophilia Treatment and Research
- Mast cells and histamine
- Porphyrin and Phthalocyanine Chemistry
- Cardiac electrophysiology and arrhythmias
- Synthesis of heterocyclic compounds
- Ferrocene Chemistry and Applications
- PI3K/AKT/mTOR signaling in cancer
- Organic and Inorganic Chemical Reactions
- Phosphodiesterase function and regulation
- Protein Interaction Studies and Fluorescence Analysis
Bristol-Myers Squibb (United States)
2010-2023
Bristol-Myers Squibb (Germany)
2004-2015
Moscow State University
2009
DuPont (United States)
1994-2001
Wilmington University
1994-2001
Experimental Station
1994-1999
University of California, Los Angeles
1993
Modification of a series pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P(1) ligand resulted in compounds with improved selectivity for relative trypsin and plasma kallikrein. Further optimization P(4) moiety led enhanced permeability reduced protein binding. The SAR pharmacokinetic profile this is described herein. These efforts culminated...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTConstrictive binding of large guests by a hemicarcerand containing four portalsMimi L. C. Quan and Donald J. CramCite this: Am. Chem. Soc. 1991, 113, 7, 2754–2755Publication Date (Print):March 1, 1991Publication History Published online1 May 2002Published inissue 1 March 1991https://pubs.acs.org/doi/10.1021/ja00007a060https://doi.org/10.1021/ja00007a060research-articleACS PublicationsRequest reuse permissionsArticle...
Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as point of convergence intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va Ca2+ on phospholipid surface platelets or endothelial cells, factor forms prothrombinase complex, which is responsible for proteolysis prothrombin to catalytically active thrombin. Thrombin, turn, catalyzes cleavage fibrinogen fibrin, thus initiating process that ultimately leads clot formation. Recently, we reported series...
Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe series tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound 1 was identified potent and selective tool compound for proof concept studies. It exhibited excellent antithrombotic in rabbit thrombosis models did not prolong times. This demonstrates mechanism animal reversible, small molecule inhibitor.
Factor XIa (FXIa) is a blood coagulation enzyme that involved in the amplification of thrombin generation. Mounting evidence suggests direct inhibition FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using variety approaches to reduce activity, including inhibitors FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On basis this potential, we targeted our efforts at identifying potent with focus on...
A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar inhibitors, further optimized with assistance from utilization structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery a amide linker found to form key hydrogen bond carbonyl Leu41 active site, resulting potent inhibitors. The series, exemplified by compound 16, had Ki =...
Thrombosis is a major cause of mortality in the industrialized world. Therefore, prevention blood coagulation has become target for new therapeutic agents. One attractive approach inhibition factor Xa (FXa), enzyme directly responsible prothrombin activation. We report series novel biaryl-substituted isoxazoline derivatives which biaryl moiety was designed to interact with S(4) aryl-binding domain FXa active site. Several compounds herein have low nanomolar affinity FXa, good vitro...
Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention blood coagulation has become major target for new therapeutic agents. One attractive approach inhibition Xa (FXa), enzyme directly responsible thrombin activation. Herein we report series isoxazoline derivatives which are potent FXa inhibitors. Optimization side chain at quaternary position ring led to SK549 showed subnanomolar potency (K(i) 0.52 nM). shows good selectivity...
A series of benzamidine isoxazoline derivatives was evaluated for their inhibitory potency against purified human factor Xa (fXa) and in a rabbit model arteriovenous shunt thrombosis antithrombotic activities, expressed as K(I) IC(50), respectively. highly significant correlation found between IC(50) (r = 0.93, P <.0001). The effects SF303 [mol. wt. 536; K(I): fXa, 6.3 nM; thrombin, 3,100 trypsin, 110 tissue plasminogen activator >20,000 plasmin, 2,500 nM] SK549 546; 0.52 400 45 >33,000 890...
Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor (Ki = 0.3 nM) having in vivo antithrombotic efficacy the rabbit AV-shunt thrombosis model (ID50 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto X-ray crystal structure tetrahydroquinoline 3 complexed FXIa. Further optimization achieved...
Razaxaban is a selective, potent, and orally bioavailable inhibitor of coagulation factor Xa. The molecule contains 1,2-benzisoxazole structure. After oral administration [<sup>14</sup>C]razaxaban to intact bile duct-cannulated rats (300 mg/kg) dogs (20 mg/kg), metabolism followed by biliary excretion was the major elimination pathway in both species, accounting for 34 44% dose, whereas urinary accounted 3 13% dose. Chromatographic separation radioactivity urine, bile, feces showed that...
Structure-activity relationship optimization of phenylalanine P1' and P2' regions with a phenylimidazole core resulted in series potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the group enhanced affinity metabolic stability. Incorporation an N-methyl piperazine amide to replace improved both potency aqueous solubility. Combination led discovery inhibitor 13 K i 0.04 nM aPTT EC2x 1.0 μM. Dose-dependent efficacy (EC50 0.53 μM) was achieved rabbit ECAT model minimal bleeding...