Thiophene-Anthranilamides as Highly Potent and Orally Available Factor Xa Inhibitors

• Published in: Journal of medicinal chemistry Vol. 50; no. 13; pp. 2967 - 2980
• Main Authors: Ye, Bin, Arnaiz, Damian O, Chou, Yuo-Ling, Griedel, Brian D, Karanjawala, Rushad, Lee, Wheeseong, Morrissey, Michael M, Sacchi, Karna L, Sakata, Steven T, Shaw, Kenneth J, Wu, Shung C, Zhao, Zuchun, Adler, Marc, Cheeseman, Sarah, Dole, William P, Ewing, Janice, Fitch, Richard, Lentz, Dao, Liang, Amy, Light, David, Morser, John, Post, Joseph, Rumennik, Galina, Subramanyam, Babu, Sullivan, Mark E, Vergona, Ron, Walters, Janette, Wang, Yi-Xin, White, Kathy A, Whitlow, Marc, Kochanny, Monica J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.06.2007; Amer Chemical Soc
• Subjects: Amides - chemical synthesis; Amides - pharmacokinetics; Amides - pharmacology; Aminopyridines - chemical synthesis; Aminopyridines - pharmacokinetics; Aminopyridines - pharmacology; Animals; Anticoagulants - chemical synthesis; Anticoagulants - pharmacokinetics; Anticoagulants - pharmacology; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Chemistry, Medicinal; Crystallography, X-Ray; Dogs; Factor Xa Inhibitors; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Male; Medical sciences; Models, Molecular; ortho-Aminobenzoates - chemical synthesis; ortho-Aminobenzoates - pharmacokinetics; ortho-Aminobenzoates - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Prothrombin Time; Rats; Rats, Wistar; Science & Technology; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - pharmacokinetics; Thiophenes - pharmacology; Venous Thrombosis - drug therapy; ARTERIAL; BINDING MODES; DESIGN; COAGULATION-FACTOR-XA; 1,2-DIBENZAMIDOBENZENE INHIBITORS; NONCOVALENT THROMBIN INHIBITORS; ANTITHROMBOTIC EFFICACY; P4 MOTIFS; 2-CARBOXYINDOLE SCAFFOLD; DISCOVERY; Rat; Coagulation Factor Xa; Anticoagulant; Pyridine derivatives; Thiophene derivatives; Structure activity relation; Antithrombotic agent; Chemical synthesis; Dog; Oxazole derivatives; Human; Fissipedia; Carnivora; Serine endopeptidases; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Organic chlorine compounds; In vitro; Peptidases; In vivo; Vertebrata; Mammalia; Animal; Hydrolases; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070125f

There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.