Author/Authors :
Theresa M. Williams، نويسنده , , Craig A. Stump، نويسنده , , Diem N. Nguyen، نويسنده , , Amy G. Quigley، نويسنده , , Ian M. Bell، نويسنده , , Steven N. Gallicchio، نويسنده , , C. Blair Zartman، نويسنده , , Bang-Lin Wan، نويسنده , , Kimberly Della Penna، نويسنده , , Priya Kunapuli، نويسنده , , Stefanie A. Kane، نويسنده , , Ken S. Koblan، نويسنده , , Scott D. Mosser، نويسنده , , Ruth Z. Rutledge، نويسنده , , Christopher Salvatore، نويسنده , , John F. Fay، نويسنده , , Joseph P. Vacca، نويسنده , , Samuel L. Graham، نويسنده ,
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 Ki = 44 nM and IC50 = 38 nM. Compound 7 was orally bioavailabile in rats and is a lead in the development of orally bioavailable CGRP antagonists for the treatment of migraine.
Keywords :
Benzodiazepinone , CGRP , CLR/RAMP1 , Migraine , CGRP receptor antagonist
