EurekaMag.com logo
+ Site Statistics
References:
52,725,316
Abstracts:
28,411,598
+ Search Articles
+ Subscribe to Site Feeds
EurekaMag Most Shared ContentMost Shared
EurekaMag PDF Full Text ContentPDF Full Text
+ PDF Full Text
Request PDF Full TextRequest PDF Full Text
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter
Follow on Google+Follow on Google+
Follow on LinkedInFollow on LinkedIn

+ Translate

Novel benzoxazole inhibitors of mPGES-1






Bioorganic & Medicinal Chemistry Letters 23(3): 907-911

Novel benzoxazole inhibitors of mPGES-1

A novel series of potent benzoxazole mPGES-1 inhibitors has been derived from a hit from a high throughput screen. Compound 37 displays mPGES-1 inhibition in an enzyme assay (0.018 μM) and PGE-2 inhibition in a cell-based assay (0.034 μM). It demonstrates 500- and 2500-fold selectivity for mPGES-1 over COX-2 and 6-keto PGF-1α, respectively. In vivo PK studies in dogs demonstrate 55% oral bioavailability and an 7 h half-life.


Accession: 054669412

PMID: 23266122

DOI: 10.1016/j.bmcl.2012.10.040



Related references

Liedtke, A.J.; Keck, P.R.W.E.F.; Lehmann, F.; Koeberle, A.; Werz, O.; Laufer, S.A., 2009: Arylpyrrolizines as inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) or as dual inhibitors of mPGES-1 and 5-lipoxygenase (5-LOX). We synthesized and evaluated inhibitors for the microsomal prostaglandin E2 synthase-1 (mPGES-1), based on the arylpyrrolizine scaffold. In a cell free mPGES-1 assay several "sulfonimides" exceeded our lead ML3000 (3) in potency. The mos...

Iranshahi, M.; Chini, M.Giovanna.; Masullo, M.; Sahebkar, A.; Javidnia, A.; Chitsazian Yazdi, M.; Pergola, C.; Koeberle, A.; Werz, O.; Pizza, C.; Terracciano, S.; Piacente, S.; Bifulco, G., 2016: Can Small Chemical Modifications of Natural Pan-inhibitors Modulate the Biological Selectivity? The Case of Curcumin Prenylated Derivatives Acting as HDAC or mPGES-1 Inhibitors. Curcumin, or diferuloylmethane, a polyphenolic molecule isolated from the rhizome of Curcuma longa, is reported to modulate multiple molecular targets involved in cancer and inflammatory processes. On the basis of its pan-inhibitory characteristic...

Mattila, S.; Tuominen, H.; Koivukangas, J.; Stenbäck, F., 2009: The terminal prostaglandin synthases mPGES-1, mPGES-2, and cPGES are all overexpressed in human gliomas. Prostaglandin E2 has been connected to processes promoting tumor growth in several human malignancies including gliomas. The terminal prostaglandin synthases mPGES-1, mPGES-2, and cPGES convert PGH2 into prostaglandin E2. The inhibition of their f...

Giannico, G.; Mendez, M.; LaPointe, M.C., 2004: Regulation of the membrane-localized prostaglandin E synthases mPGES-1 and mPGES-2 in cardiac myocytes and fibroblasts. The proinflammatory mediator cyclooxygenase (COX)-2 and its product PGE2 are induced in the ischemic heart, contributing to inflammatory cell infiltration, fibroblast proliferation, and cardiac hypertrophy. PGE2 synthesis coupled to COX-2 involves...

Radi, Z.A.; Ostroski, R., 2007: Pulmonary and cardiorenal cyclooxygenase-1 (COX-1), -2 (COX-2), and microsomal prostaglandin E synthase-1 (mPGES-1) and -2 (mPGES-2) expression in a hypertension model. Hypertensive mice that express the human renin and angiotensinogen genes are used as a model for human hypertension because they develop hypertension secondary to increased renin-angiotensin system activity. Our study investigated the cellular lo...

Radi, Z., A.; Ostroski, R., 2007: Pulmonary and cardiorenal cyclooxygenase-1 (COX-1),-2 (COX-2), and microsomal prostaglandin E synthase-1 (mPGES-1) and-2 (mPGES-2) expression in a hypertension model. Hypertensive mice that express the human renin and angiotensinogen genes are used as a model for human hypertension because they develop hypertension secondary to increased renin-angiotensin system activity. Our study investigated the cellular lo...

Leclerc, P.; Idborg, H.; Spahiu, L.; Larsson, C.; Nekhotiaeva, N.; Wannberg, J.; Stenberg, P.; Korotkova, M.; Jakobsson, P-Johan., 2014: Characterization of a human and murine mPGES-1 inhibitor and comparison to mPGES-1 genetic deletion in mouse models of inflammation. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibition has been suggested as an alternative to cyclooxygenase (COX) inhibition in the treatment of pain and inflammation. We characterized a selective inhibitor of mPGES-1 activity (compound III)...

Gudis, K.; Tatsuguchi, A.; Wada, K.; Futagami, S.; Nagata, K.; Hiratsuka, T.; Shinji, Y.; Miyake, K.; Tsukui, T.; Fukuda, Y.; Sakamoto, C., 2004: Microsomal prostaglandin E synthase (mPGES)-1, mPGES-2 and cytosolic PGES expression in human gastritis and gastric ulcer tissue. Recently, three different prostaglandin E2 synthases have been identified: microsomal prostaglandin E synthase (mPGES)-1, cytosolic PGES (cPGES), and mPGES-2; however, their role and connection to cyclooxygenase (COX)-2 in the gastric ulcer repair...

Chang, H-Hua.; Meuillet, E.J., 2012: Identification and development of mPGES-1 inhibitors: where we are at?. Microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal synthase responsible for the synthesis of the pro-tumorigenic prostaglandin E(2) (PGE(2)). mPGES-1 is overexpressed in a wide variety of cancers. Since its discovery in 1997 by Bengt...

Park, S-Jun.; Han, S-Gu.; Ahsan, H.Muhammad.; Lee, K.; Lee, J.Yeol.; Shin, J-Sun.; Lee, K-Tae.; Kang, N-Suk.; Yu, Y.Gyu., 2013: Identification of novel mPGES-1 inhibitors through screening of a chemical library. Human microsomal prostaglandin E synthase-1 (mPGES-1) is an emerging drug target for inflammatory disorders and cancer suppression. Therefore, it is crucially important to discover mPGES-1 inhibitors with novel structural scaffolds for the develop...