Aroylguanidine-based factor Xa inhibitors: The discovery of BMS-344577

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 24; pp. 6882 - 6889
• Main Authors: Shi, Yan, Li, Chi, O’Connor, Stephen P., Zhang, Jing, Shi, Mengxiao, Bisaha, Sharon N., Wang, Ying, Sitkoff, Doree, Pudzianowski, Andrew T., Huang, Christine, Klei, Herbert E., Kish, Kevin, Yanchunas, Joseph, Liu, Eddie C.-K., Hartl, Karen S., Seiler, Steve M., Steinbacher, Thomas E., Schumacher, William A., Atwal, Karnail S., Stein, Philip D.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.12.2009; Elsevier
• Subjects: Anticoagulants - chemistry; Anticoagulants - pharmacology; Aroylguanidine; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; CYP3A4 inhibition; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Discovery; Factor Xa inhibitor; Factor Xa Inhibitors; Guanidines - chemistry; Guanidines - pharmacology; Humans; Inhibitory Concentration 50; Medical sciences; Orally active; Pharmacology. Drug treatments; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Structure-Activity Relationship; CYP3A4 inhibition; Orally active; Factor Xa inhibitor; Aroylguanidine; Intravenous administration; Isozyme; Lactam; Cardiovascular disease; Coagulation Factor Xa; Anticoagulant; Acetylsalicylic acid; Modeling; Pyrrolidine derivatives; Pyridine derivatives; Vascular disease; Structure activity relation; Molecular model; Antithrombotic agent; Chemical synthesis; Drug combination; Unspecific monooxygenase; Serine endopeptidases; Enzyme; Cytochrome P450; Oral administration; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; Thrombosis; Peptidases; In vivo; Chemotherapy; Experimental disease; Treatment; Animal; Hydrolases; Carboxamide; Drug-metabolizing enzyme; Oxidoreductases; Benzofuran derivatives; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.10.084

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 IC50=4nM, EC2×PT=7μM). However, the potent CYP3A4 inhibition activity (IC50=0.3μM) 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, IC50=9nM, EC2×PT=2.5μM), 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.