Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists.
A rapid analogue approach to identification of spirohydantoin-based CGRP antagonists provided novel, low molecular weight leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption. Optimization provided compound 12, a potent CGRP receptor antagonist (K(i)=21nM) with good oral bioavailability in three species.
Bell
Ian M
IM
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. ian_bell@merck.com
Bednar
Rodney A
RA
Fay
John F
JF
Gallicchio
Steven N
SN
Hochman
Jerome H
JH
McMasters
Daniel R
DR
Miller-Stein
Cynthia
C
Moore
Eric L
EL
Mosser
Scott D
SD
Pudvah
Nicole T
NT
Quigley
Amy G
AG
Salvatore
Christopher A
CA
Stump
Craig A
CA
Theberge
Cory R
CR
Wong
Bradley K
BK
Zartman
C Blair
CB
Zhang
Xu-Fang
XF
Kane
Stefanie A
SA
Graham
Samuel L
SL
Vacca
Joseph P
JP
Williams
Theresa M
TM
D000284:Administration, Oral; D001562:Benzimidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002460:Cell Line; D006801:Humans; D006827:Hydantoins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007668:Kidney; D008958:Models, Molecular; D015394:Molecular Structure; D013141:Spiro Compounds / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D006827:Hydantoins; D013141:Spiro Compounds