Identification of novel glycine sulfonamide antagonists for the EP1 receptor.
A high-throughput screen targeting the EP(1) receptor identified non-acidic glycine sulfonamide derivative 2a with a pK(i) of 6.2. Analogue synthesis allowed a thorough investigation of the structure-activity relationship (SAR) and led to a 100-fold increase in recombinant potency.
McKeown
Stephen C
SC
Molecular Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Steve.C.McKeown@gsk.com
Hall
Adrian
A
Blunt
Richard
R
Brown
Susan H
SH
Chessell
Iain P
IP
Chowdhury
Anita
A
Giblin
Gerard M P
GM
Healy
Mark P
MP
Johnson
Matthew R
MR
Lorthioir
Olivier
O
Michel
Anton D
AD
Naylor
Alan
A
Lewell
Xiao
X
Roman
Shilina
S
Watson
Stephen P
SP
Winchester
Wendy J
WJ
Wilson
Richard J
RJ
D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D018684:Glycine Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*
D018684:Glycine Agents; D007202:Indicators and Reagents; C545635:PTGER1 protein, human; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013449:Sulfonamides; D003577:Cytochrome P-450 Enzyme System; D015232:Dinoprostone