Non-peptide calcitonin gene-related peptide receptor antagonists from a benzodiazepinone lead.
High-throughput screening of the Merck sample collection identified benzodiazepinone tetralin-spirohydantoin 1 as a CGRP receptor antagonist with micromolar activity. Comparing the structure of 1 with those of earlier peptide-based antagonists such as BIBN 4096 BS, a key hydrogen bond donor-acceptor pharmacophore was hypothesized. Subsequent structure activity studies supported this hypothesis and led to benzodiazepinone piperidinyldihydroquinazolinone 7, CGRP receptor K(i)=44nM and IC(50)=38nM. Compound 7 was orally bioavailabile in rats and is a lead in the development of orally bioavailable CGRP antagonists for the treatment of migraine.
Williams
Theresa M
TM
Department of Medicinal Chemistry Merck & Co., West Point, PA 19486, USA. theresa_williams@merck.com
Stump
Craig A
CA
Nguyen
Diem N
DN
Quigley
Amy G
AG
Bell
Ian M
IM
Gallicchio
Steven N
SN
Zartman
C Blair
CB
Wan
Bang-Lin
BL
Penna
Kimberly Della
KD
Kunapuli
Priya
P
Kane
Stefanie A
SA
Koblan
Ken S
KS
Mosser
Scott D
SD
Rutledge
Ruth Z
RZ
Salvatore
Christopher
C
Fay
John F
JF
Vacca
Joseph P
JP
Graham
Samuel L
SL
D000818:Animals; D001570:Benzodiazepinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002460:Cell Line; D006801:Humans; D006860:Hydrogen Bonding; D051381:Rats; D013329:Structure-Activity Relationship
D001570:Benzodiazepinones; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists