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Bioorg Med Chem Lett. 2019 Sep 15;29(18):2700-2705. doi: 10.1016/j.bmcl.2019.07.007. Epub 2019 Jul 24.

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

Author information

1
Bayer AG, Pharmaceuticals R&D, 13342 Berlin, Germany. Electronic address: marcus.koppitz@bayer.com.
2
Bayer AG, Pharmaceuticals R&D, 13342 Berlin, Germany.
3
Evotec SE, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
4
Evotec (UK) Ltd, 112-114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.

Abstract

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.

KEYWORDS:

PGE(2); PTGES; Pain; Prostaglandin pathway; mPGES-1

PMID:
31362919
DOI:
10.1016/j.bmcl.2019.07.007

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