Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design

被引：41

作者：

Jones, Spencer B. ^{[1
]}

Pfeifer, Lance A. ^{[1
]}

Bleisch, Thomas J. ^{[1
]}

Beauchamp, Thomas J. ^{[1
]}

Durbin, Jim D. ^{[1
]}

Klimkowski, V. Joseph ^{[1
]}

Hughes, Norman E. ^{[1
]}

Rito, Christopher J. ^{[1
]}

Dao, Yen ^{[1
]}

Gruber, Joseph M. ^{[1
,2
]}

Bui, Hai ^{[1
]}

Chambers, Mark G. ^{[1
]}

Chandrasekhar, Srinivasan ^{[1
]}

Lin, Chaohua ^{[1
]}

McCann, Denis J. ^{[1
]}

Mudra, Daniel R. ^{[1
]}

Oskins, Jennifer L. ^{[1
]}

Swearingen, Craig A. ^{[1
]}

Thirunavukkarasu, Kannan ^{[1
]}

Norman, Bryan H. ^{[1
]}

机构：

[1] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA

[2] Dow AgroSci, Zionsville, IN 46268 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 09期

关键词：

Autotaxin; tool molecule; osteoarthritis; LPA; LYSOPHOSPHATIDIC ACID PRODUCTION; ARTHRITIS; MOTILITY; SITE; LPA;

D O I：

10.1021/acsmedchemlett.6b00207

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC50 = 2 nM), PK properties, and a robust PK/PD relationship.

引用

页码：857 / 861

页数：5

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