5T36

Crystal structure of mPGES-1 bound to inhibitor

Summary for 5T36

• Entry DOI: 10.2210/pdb5t36/pdb
• Descriptor: Prostaglandin E synthase, 4-chloro-2-[({(1S,2S)-2-[(2,2-dimethylpropanoyl)amino]cyclopentyl}methyl)amino]benzoic acid, GLUTATHIONE, ... (6 entities in total)
• Functional Keywords: prostaglandin, enzyme, integral membrane protein, alpha helix, membrane protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 18746.70

Authors

Luz, J.G.,Antonysamy, S.,Partridge, K.,Fisher, M. (deposition date: 2016-08-24, release date: 2017-03-01, Last modification date: 2024-03-06)

Primary citation

Partridge, K.M.,Antonysamy, S.,Bhattachar, S.N.,Chandrasekhar, S.,Fisher, M.J.,Fretland, A.,Gooding, K.,Harvey, A.,Hughes, N.E.,Kuklish, S.L.,Luz, J.G.,Manninen, P.R.,McGee, J.E.,Mudra, D.R.,Navarro, A.,Norman, B.H.,Quimby, S.J.,Schiffler, M.A.,Sloan, A.V.,Warshawsky, A.M.,Weller, J.M.,York, J.S.,Yu, X.P.
Discovery and characterization of [(cyclopentyl)ethyl]benzoic acid inhibitors of microsomal prostaglandin E synthase-1.
Bioorg. Med. Chem. Lett., 27:1478-1483, 2017

PubMed Abstract: We describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led initially to the identification of anthranilic acid 5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000×, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of [(cyclopentyl)ethyl]benzoic acid compound 16 for clinical studies. Compound 16 showed an IC of 24nM for inhibition of PGE formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC in both rat (5mg/kg) and dog (3mg/kg) for over twelve hours.

PubMed: 28190634
DOI: 10.1016/j.bmcl.2016.11.011

Experimental method

X-RAY DIFFRACTION (1.4 Å)