A new class of bradykinin B1 receptor antagonists with high oral bioavailability and minimal PXR activity.
The design and synthesis of a novel class of human bradykinin B1 antagonists featuring difluoroethyl ether and isoxazole carboxamide moieties are disclosed. Compound 7g displayed excellent pharmacokinetic properties, efficient ex vivo receptor occupancy, and low potential for P450 induction via PXR activation.
Feng
Dong-Mei
DM
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
DiPardo
Robert M
RM
Wai
Jenny M
JM
Chang
Ronald K
RK
Di Marco
Christina N
CN
Murphy
Kathy L
KL
Ransom
Richard W
RW
Reiss
Duane R
DR
Tang
Cuyue
C
Prueksaritanont
Thomayant
T
Pettibone
Douglas J
DJ
Bock
Mark G
MG
Kuduk
Scott D
SD
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D065169:Bradykinin B1 Receptor Antagonists; D004285:Dogs; D006801:Humans; D007555:Isoxazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008253:Macaca mulatta; D000077297:Pregnane X Receptor; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000187:drug effects*
D065169:Bradykinin B1 Receptor Antagonists; D007555:Isoxazoles; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid