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5k0i

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mpges1 bound to an inhibitor

Structural highlights

5k0i is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.3Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PTGES_HUMAN Catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2).^[1]

Publication Abstract from PubMed

Here we report on novel, potent 3,3-dimethyl substituted N-aryl piperidine inhibitors of microsomal prostaglandin E synthases-1(mPGES-1). Example 14 potently inhibited PGE2 synthesis in an ex vivo human whole blood (HWB) assay with an IC50 of 7nM. In addition, 14 had no activity in human COX-1 or COX-2 assays at 30muM, and failed to inhibit human mPGES-2 at 62.5muM in a microsomal prep assay. These data are consistent with selective mPGES-1-mediated reduction of PGE2. In dog, 14 had oral bioavailability (74%), clearance (3.62mL/(min*kg)) and volume of distribution (Vd,ss=1.6L/kg) values within our target ranges. For these reasons, 14 was selected for further study.

Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors.,Kuklish SL, Antonysamy S, Bhattachar SN, Chandrasekhar S, Fisher MJ, Fretland AJ, Gooding K, Harvey A, Hughes NE, Luz JG, Manninen PR, McGee JE, Navarro A, Norman BH, Partridge KM, Quimby SJ, Schiffler MA, Sloan AV, Warshawsky AM, York JS, Yu XP Bioorg Med Chem Lett. 2016 Oct 1;26(19):4824-8. doi: 10.1016/j.bmcl.2016.08.023. , Epub 2016 Aug 10. PMID:27554445^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Jegerschold C, Pawelzik SC, Purhonen P, Bhakat P, Gheorghe KR, Gyobu N, Mitsuoka K, Morgenstern R, Jakobsson PJ, Hebert H. Structural basis for induced formation of the inflammatory mediator prostaglandin E2. Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11110-5. Epub 2008 Aug 5. PMID:18682561 doi:0802894105
↑ Kuklish SL, Antonysamy S, Bhattachar SN, Chandrasekhar S, Fisher MJ, Fretland AJ, Gooding K, Harvey A, Hughes NE, Luz JG, Manninen PR, McGee JE, Navarro A, Norman BH, Partridge KM, Quimby SJ, Schiffler MA, Sloan AV, Warshawsky AM, York JS, Yu XP. Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors. Bioorg Med Chem Lett. 2016 Oct 1;26(19):4824-8. doi: 10.1016/j.bmcl.2016.08.023. , Epub 2016 Aug 10. PMID:27554445 doi:http://dx.doi.org/10.1016/j.bmcl.2016.08.023