title: Non-peptide calcitonin gene-related peptide receptor antagonists from a benzodiazepinone lead.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry Merck & Co., West Point, PA 19486, USA. theresa_williams@merck.com
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Williams
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stump
authors.forename: Diem N
authors.initials: DN
authors.lastname: Nguyen
authors.forename: Amy G
authors.initials: AG
authors.lastname: Quigley
authors.forename: Ian M
authors.initials: IM
authors.lastname: Bell
authors.forename: Steven N
authors.initials: SN
authors.lastname: Gallicchio
authors.forename: C Blair
authors.initials: CB
authors.lastname: Zartman
authors.forename: Bang-Lin
authors.initials: BL
authors.lastname: Wan
authors.forename: Kimberly Della
authors.initials: KD
authors.lastname: Penna
authors.forename: Priya
authors.initials: P
authors.lastname: Kunapuli
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Kane
authors.forename: Ken S
authors.initials: KS
authors.lastname: Koblan
authors.forename: Scott D
authors.initials: SD
authors.lastname: Mosser
authors.forename: Ruth Z
authors.initials: RZ
authors.lastname: Rutledge
authors.forename: Christopher
authors.initials: C
authors.lastname: Salvatore
authors.forename: John F
authors.initials: JF
authors.lastname: Fay
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
mesh_terms: 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
chemical_list: D001570:Benzodiazepinones; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists