title: Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa.
abstract: Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification of the carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa binding activity. Exceptional potency of the series prompted an investigation of the neutral P1 moieties that resulted in the identification of the p-methoxyphenyl P1, which retained factor Xa binding affinity and good oral bioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P4 ring with a neutral heterocycle culminated in the discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokinetic profile relative to 4.
authors.affiliation: Discovery Chemistry, Research and Development, Bristol-Myers Squibb Company, 31 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, USA. donald.pinto@bms.com
authors.forename: Donald J P
authors.initials: DJ
authors.lastname: Pinto
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Orwat
authors.forename: Stephanie
authors.initials: S
authors.lastname: Koch
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.forename: Richard S
authors.initials: RS
authors.lastname: Alexander
authors.forename: Angela
authors.initials: A
authors.lastname: Smallwood
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Kan
authors.initials: K
authors.lastname: He
authors.forename: Baomin
authors.initials: B
authors.lastname: Xin
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001777:Blood Coagulation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004285:Dogs; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban