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Discovery and characterization of [(cyclopentyl)ethyl]benzoic acid inhibitors of microsomal prostaglandin E synthase-1 |
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| Authors: | Katherine M Partridge Stephen Antonysamy Shobha N Bhattachar Srinivasan Chandrasekhar Matthew J Fisher Adrian Fretland Karen Gooding Anita Harvey Norman E Hughes Steven L Kuklish John G Luz Peter R Manninen James E McGee Daniel R Mudra Antonio Navarro Bryan H Norman Steven J Quimby Matthew A Schiffler Xiao-Peng Yu |
| Institution: | 1. Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA;2. Eli Lilly Biotechnology Center, San Diego, CA 92121, USA;3. Retired;4. Present/Permanent address: Discovery Sciences, Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA |
| 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 IC80 of 24 nM for inhibition of PGE2 formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC80 in both rat (5 mg/kg) and dog (3 mg/kg) for over twelve hours. |
| Keywords: | mPGES-1 Prostaglandin pathway Bioavailability Biomarker |
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