From virtual to clinical: The discovery of PGN-1531, a novel antagonist of the prostanoid EP4 receptor.
In this Letter, we present the results of a hit-finding and lead optimization programme against the EP4 receptor (EP4R). In a short time period, we were able to discover five structurally diverse series of hit compounds using a combination of virtual screening methods. The most favoured hit, compound 6, was demonstrated to be a competitive antagonist of the EP4R. Compound 73 was identified following several rounds of optimization, which centred on improving both the primary EP4R affinity and selectivity against the related EP2R as well as the aqueous solubility. This work culminated in the preparation of PGN-1531, the sodium salt of 73, which showed a marked improvement in solubility (>10 mg/mL). PGN-1531 is a potent and selective antagonist at EP4Rs in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation.
Argenta, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom. Electronic address: jon.sutton@crl.com.
Jon
J
Sutton
Argenta, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
David E
DE
Clark
Argenta, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
Christopher
C
Higgs
Argenta, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
Marcel J
MJ
de Groot
Argenta, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
Neil V
NV
Harris
Argenta, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
Andrea
A
Taylor
Argenta, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom.
Peter M
PM
Lockey
BTG International Ltd, 5 Fleet Place, London EC4M 7RD, United Kingdom.
Karen
K
Maubach
Pharmagene plc, 2 Orchard Road, Royston, Hertfordshire SG8 5HD, United Kingdom.
Amanda
A
Woodrooffe
Pharmagene plc, 2 Orchard Road, Royston, Hertfordshire SG8 5HD, United Kingdom.
Richard J
RJ
Davis
Pharmagene plc, 2 Orchard Road, Royston, Hertfordshire SG8 5HD, United Kingdom.
Robert A
RA
Coleman
Pharmagene plc, 2 Orchard Road, Royston, Hertfordshire SG8 5HD, United Kingdom.
Kenneth L
KL
Clark
D001921:Brain / Q000098:blood supply; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008881:Migraine Disorders / Q000188:drug therapy; D008958:Models, Molecular; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D008024:Ligands; D058309:Receptors, Prostaglandin E, EP4 Subtype
Cerebral vasodilatation; EP(4) receptor antagonist; Hit-finding; Lead optimization; Migraine