1294496-58-4Relevant articles and documents
Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin e Synthase-1 Inhibitors
Schiffler, Matthew A.,Antonysamy, Stephen,Bhattachar, Shobha N.,Campanale, Kristina M.,Chandrasekhar, Srinivasan,Condon, Bradley,Desai, Prashant V.,Fisher, Matthew J.,Groshong, Christopher,Harvey, Anita,Hickey, Michael J.,Hughes, Norman E.,Jones, Scott A.,Kim, Euibong J.,Kuklish, Steven L.,Luz, John G.,Norman, Bryan H.,Rathmell, Richard E.,Rizzo, John R.,Seng, Thomas W.,Thibodeaux, Stefan J.,Woods, Timothy A.,York, Jeremy S.,Yu, Xiao-Peng
, p. 194 - 205 (2016/01/28)
As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 μM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8·H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.
BICYCLIC COMPOUNDS AS mPGES-1 INHIBITORS
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Paragraph 0275; 0290; 0302, (2013/08/28)
The present disclosure is directed to compounds of formula (I), and pharmaceutically acceptable salts thereof, as mPGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases.
SUBSTITUTED BICYCLIC HETEROARYL COMPOUNDS AS mPGES-1 INHIBITORS
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Page/Page column 78, (2013/03/28)
The present invention relates to bicyclic compounds of formula (I) or pharmaceutically acceptable salt thereof as mPGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (m PGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthama, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases. (I)
