title: Discovery of 1-[3-(aminomethyl)phenyl]-N-3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa.
abstract: Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K(i) = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.
authors.affiliation: DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA. Donald.J.Pinto@dupontpharma.com
authors.forename: D J
authors.initials: DJ
authors.lastname: Pinto
authors.forename: M J
authors.initials: MJ
authors.lastname: Orwat
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: J M
authors.initials: JM
authors.lastname: Fevig
authors.forename: M L
authors.initials: ML
authors.lastname: Quan
authors.forename: E
authors.initials: E
authors.lastname: Amparo
authors.forename: J
authors.initials: J
authors.lastname: Cacciola
authors.forename: K A
authors.initials: KA
authors.lastname: Rossi
authors.forename: R S
authors.initials: RS
authors.lastname: Alexander
authors.forename: A M
authors.initials: AM
authors.lastname: Smallwood
authors.forename: J M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: L
authors.initials: L
authors.lastname: Liang
authors.forename: B J
authors.initials: BJ
authors.lastname: Aungst
authors.forename: M R
authors.initials: MR
authors.lastname: Wright
authors.forename: R M
authors.initials: RM
authors.lastname: Knabb
authors.forename: P C
authors.initials: PC
authors.lastname: Wong
authors.forename: R R
authors.initials: RR
authors.lastname: Wexler
authors.forename: P Y
authors.initials: PY
authors.lastname: Lam
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C421624:1-(3-(aminomethyl)phenyl)-N-(3-fluoro-2'-(methylsulfonyl)(1,1'-biphenyl)-4-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011720:Pyrazoles; D015842:Serine Proteinase Inhibitors; D013450:Sulfones