A new class of bradykinin B1 receptor antagonists with high oral bioavailability and minimal PXR activity

Dong-Mei Feng; Robert M DiPardo; Jenny M Wai; Ronald K Chang; Christina N Di Marco; Kathy L Murphy; Richard W Ransom; Duane R Reiss; Cuyue Tang; Thomayant Prueksaritanont; Douglas J Pettibone; Mark G Bock; Scott D Kuduk

doi:10.1016/j.bmcl.2007.11.057

A new class of bradykinin B1 receptor antagonists with high oral bioavailability and minimal PXR activity

Bioorg Med Chem Lett. 2008 Jan 15;18(2):682-7. doi: 10.1016/j.bmcl.2007.11.057.

Authors

Dong-Mei Feng¹, Robert M DiPardo, Jenny M Wai, Ronald K Chang, Christina N Di Marco, Kathy L Murphy, Richard W Ransom, Duane R Reiss, Cuyue Tang, Thomayant Prueksaritanont, Douglas J Pettibone, Mark G Bock, Scott D Kuduk

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.

PMID: 18240388
DOI: 10.1016/j.bmcl.2007.11.057

Abstract

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.

MeSH terms

Administration, Oral
Animals
Biological Availability
Bradykinin B1 Receptor Antagonists*
Dogs
Humans
Isoxazoles / pharmacokinetics
Isoxazoles / pharmacology*
Macaca mulatta
Pregnane X Receptor
Rats
Rats, Sprague-Dawley
Receptors, Steroid / drug effects*

Substances

Bradykinin B1 Receptor Antagonists
Isoxazoles
Pregnane X Receptor
Receptors, Steroid