title: Identification of a novel conformationally constrained glucagon receptor antagonist.
abstract: Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences.
authors.affiliation: Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States. Electronic address: esther.lee2@pfizer.com.
authors.forename: Esther C Y
authors.initials: EC
authors.lastname: Lee
authors.affiliation: Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States.
authors.forename: Meihua
authors.initials: M
authors.lastname: Tu
authors.affiliation: Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Stevens
authors.affiliation: Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, CT 06340, United States.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Bian
authors.affiliation: Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, CT 06340, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Aspnes
authors.affiliation: Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, CT 06340, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Perreault
authors.affiliation: Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Sammons
authors.affiliation: Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, CT 06340, United States.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wright
authors.affiliation: Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States.
authors.forename: John
authors.initials: J
authors.lastname: Litchfield
authors.affiliation: Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.affiliation: Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, CT 06340, United States.
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, CT 06340, United States.
authors.forename: Mary T
authors.initials: MT
authors.lastname: Didiuk
authors.affiliation: Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States.
authors.forename: David C
authors.initials: DC
authors.lastname: Ebner
authors.affiliation: Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Filipski
authors.affiliation: Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, CT 06340, United States.
authors.forename: Janice
authors.initials: J
authors.lastname: Brown
authors.affiliation: Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, CT 06340, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Atkinson
authors.affiliation: Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Pfefferkorn
authors.affiliation: Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, CT 06340, United States.
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D002478:Cells, Cultured; D004285:Dogs; D008024:Ligands; D008968:Molecular Conformation; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011485:Protein Binding / Q000187:drug effects; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
chemical_list: D001549:Benzamides; D008024:Ligands; D011743:Pyrimidines; D018027:Receptors, Glucagon
keywords: Diabetes mellitus; Glucagon receptor antagonist; Metabolite; Physicochemical properties