title: Structure-based design of novel guanidine/benzamidine mimics: potent and orally bioavailable factor Xa inhibitors as novel anticoagulants.
abstract: As part of an ongoing effort to prepare orally active factor Xa inhibitors using structure-based drug design techniques and molecular recognition principles, a systematic study has been performed on the pharmacokinetic profile resulting from replacing the benzamidine in the P1 position with less basic benzamidine mimics or neutral residues. It is demonstrated that lowering the pK(a) of the P1 ligand resulted in compounds (3-benzylamine, 15a; 1-aminoisoquinoline, 24a; 3-aminobenzisoxazole, 23a; 3-phenylcarboxamide, 22b; and 4-methoxyphenyl, 22a) with improved pharmacokinetic features mainly as a result of decreased clearance, increased volume of distribution, and enhanced oral absorption. This work resulted in a series of potent and orally bioavailable factor Xa inhibitors that ultimately led to the discovery of SQ311, 24a. SQ311, which utilizes a 1-aminoisoquinoline as the P1 ligand, inhibits factor Xa with a K(i) of 0.33 nM and demonstrates both good in vivo antithrombotic efficacy and oral bioavailability.
authors.affiliation: Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08542-5400, USA. patrick.lam@bms.com
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
authors.forename: Charles G
authors.initials: CG
authors.lastname: Clark
authors.forename: Renhua
authors.initials: R
authors.lastname: Li
authors.forename: Donald J P
authors.initials: DJ
authors.lastname: Pinto
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Orwat
authors.forename: Robert A
authors.initials: RA
authors.lastname: Galemmo
authors.forename: John M
authors.initials: JM
authors.lastname: Fevig
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Teleha
authors.forename: Richard S
authors.initials: RS
authors.lastname: Alexander
authors.forename: Angela M
authors.initials: AM
authors.lastname: Smallwood
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Wright
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Bai
authors.forename: Kan
authors.initials: K
authors.lastname: He
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001550:Benzamidines / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D065427:Factor Xa Inhibitors; D006146:Guanidines / Q000494:pharmacology*; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D007408:Intestinal Absorption; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D018716:Molecular Mimicry; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D013917:Thrombin / Q000737:chemistry
chemical_list: C478604:1-(1-amino-7-isoquinolyl)-N-(2'-(aminosulfonyl)-1,1'-biphenyl-4-yl)-3-methyl-1H-pyrazole-5-carboxamide; D000925:Anticoagulants; D001550:Benzamidines; D065427:Factor Xa Inhibitors; D006146:Guanidines; D007202:Indicators and Reagents; D007546:Isoquinolines; D013449:Sulfonamides; D013917:Thrombin