Potent oxadiazole CGRP receptor antagonists for the potential treatment of migraine.
A pharmacophore model was built, based on known CGRP receptor antagonists, and this was used to aid the identification of novel leads. Analogues were designed, modelled and synthesised which incorporated alternative 'LHS' fragments linked via either an amide or urea to a privileged 'RHS' fragment commonly found in CGRP receptor antagonists. As a result a novel series of oxadiazole CGRP receptor antagonists has been identified and the subsequent optimisation to enhance both potency and bioavailability is presented.
Nichols
Paula L
PL
Department of Medicinal Chemistry, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. paula.l.nichols@gsk.com
Brand
Jonathan
J
Briggs
Michael
M
D'Angeli
Mathilde
M
Farge
Jennifer
J
Garland
Stephen L
SL
Goldsmith
Paul
P
Hutchings
Rio
R
Kilford
Ian
I
Li
Ho Y
HY
MacPherson
David
D
Nimmo
Fiona
F
Sanderson
Francis Dominic
FD
Sehmi
Sanjeet
S
Shuker
Nicola
N
Skidmore
John
J
Stott
Michael
M
Sweeting
Jennifer
J
Tajuddin
Hasmi
H
Takle
Andrew K
AK
Trani
Giancarlo
G
Wall
Ian D
ID
Ward
Robert
R
Wilson
David M
DM
Witty
David
D
D000284:Administration, Oral; D000818:Animals; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D015195:Drug Design; D008881:Migraine Disorders / Q000188:drug therapy*; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D010069:Oxadiazoles