Partridge Katherine M, Antonysamy Stephen, Bhattachar Shobha N, Chandrasekhar Srinivasan, Fisher Matthew J, Fretland Adrian, Gooding Karen, Harvey Anita, Hughes Norman E, Kuklish Steven L, Luz John G, Manninen Peter R, McGee James E, Mudra Daniel R, Navarro Antonio, Norman Bryan H, Quimby Steven J, Schiffler Matthew A, Sloan Ashley V, Warshawsky Alan M, Weller Jennifer M, York Jeremy S, Yu Xiao-Peng
Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
Eli Lilly Biotechnology Center, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2017 Mar 15;27(6):1478-1483. doi: 10.1016/j.bmcl.2016.11.011. Epub 2016 Nov 7.
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.
我们描述了一类新型的酸性mPGES-1抑制剂，其具有纳摩尔级的酶活性和人全血（HWB）效力。合理设计与基于结构的设计相结合，最初鉴定出邻氨基苯甲酸5，一种具有微摩尔级HWB效力的mPGES-1抑制剂。对5进行结构修饰，使HWB效力提高了1000多倍，降低了CYP2C9单点抑制作用，并改善了大鼠清除率，这导致选择[(环戊基)乙基]苯甲酸化合物16进行临床研究。化合物16在体外对脂多糖刺激的HWB中PGE形成的抑制作用的IC为24nM。单次口服剂量导致16在大鼠（5mg/kg）和狗（3mg/kg）中的血浆浓度超过其HWB IC达十二小时以上。
