Discovery of brain penetrant, soluble, pyrazole amide EP1 receptor antagonists.
We describe the discovery of a series of pyrazole amide EP(1) receptor antagonists with good aqueous solubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic group in the region of the molecule previously occupied by a carboxylic acid, which was known to be a key element of the pharmacophore. This study led to the identification of compounds such as 4h, 4j and 10b which demonstrated brain-to-blood ratios of 0.8:1-2.0:1 in addition to good solubility and metabolic stability.
Hall
Adrian
A
Neurolosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. adrian.2.hall@gsk.com
Billinton
Andy
A
Bristow
Alan K
AK
Brown
Susan H
SH
Chowdhury
Anita
A
Cutler
Leanne
L
Giblin
Gerard M P
GM
Goldsmith
Paul
P
Hayhow
Thomas G
TG
Kilford
Ian R
IR
Naylor
Alan
A
Passingham
Barry
B
Rawlings
D Anthony
DA
D000577:Amides / Q000737:chemistry; D001921:Brain / Q000187:drug effects*; D002264:Carboxylic Acids / Q000737:chemistry; D002490:Central Nervous System / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry*; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D012995:Solubility; D013329:Structure-Activity Relationship
D000577:Amides; D002264:Carboxylic Acids; D007546:Isoquinolines; C545635:PTGER1 protein, human; D011720:Pyrazoles; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; C039109:isoquinoline