Discovery and optimization of pyridyl-cycloalkyl-carboxylic acids as inhibitors of microsomal prostaglandin E synthase-1 for the treatment of endometriosis

[Display omitted] Here we report on novel and potent pyridyl-cycloalkyl-carboxylic acid inhibitors of microsomal prostaglandin E synthase-1 (PTGES). PTGES produces, as part of the prostaglandin pathway, prostaglandin E2 which is a well-known driver for pain and inflammation. This fact together with...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2019-09, Vol.29 (18), p.2700-2705
Main Authors: Koppitz, Marcus, Bräuer, Nico, Ter Laak, Antonius, Irlbacher, Horst, Rotgeri, Andrea, Coelho, Anne-Marie, Walter, Daryl, Steinmeyer, Andreas, Zollner, Thomas M., Peters, Michaele, Nagel, Jens
Format: Article
Language:English
Subjects:
mPGES-1
Pain
PGE2
Prostaglandin pathway
PTGES
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Summary:[Display omitted] Here we report on novel and potent pyridyl-cycloalkyl-carboxylic acid inhibitors of microsomal prostaglandin E synthase-1 (PTGES). PTGES produces, as part of the prostaglandin pathway, prostaglandin E2 which is a well-known driver for pain and inflammation. This fact together with the observed upregulation of PTGES during inflammation suggests that blockade of the enzyme might provide a beneficial treatment option for inflammation related conditions such as endometriosis. Compound 5a, a close analogue of the screening hit, potently inhibited PTGES in vitro, displayed excellent PK properties in vitro and in vivo and demonstrated efficacy in a CFA-induced pain model in mice and in a rat dyspareunia endometriosis model and was therefore selected for further studies.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2019.07.007