Serendipity in drug-discovery: a new series of 2-(benzyloxy)benzamides as TRPM8 antagonists.
A new series of 2-(benzyloxy)benzamides are presented that are potent functional antagonists of TRPM8 and possess improved LipE and LE compared to the original lead. They were discovered through a series of compound libraries and we present a powerful visualization method for the chemical space explored with each library. Remarkably this new series originated from the highest risk design strategy where compounds were synthesised with the least degree of similarity to the lead structure.
Worldwide Medicinal Chemistry, Pfizer Neusentis, Granta Park, Great Abington, Cambridge CB21 6GS, UK. Electronic address: Alan.D.Brown@pfizer.com.
Alan
A
Brown
David
D
Ellis
David A
DA
Favor
Tony
T
Kirkup
Wolfgang
W
Klute
Malcolm
M
MacKenny
Gordon
G
McMurray
Adam
A
Stennett
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D051381:Rats; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors*
D001549:Benzamides; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; C498947:Trpm8 protein, rat
1,3-Diamino cyclohexane; Lead hopping; Library design; Multi-dimensional scaling; TRPM8