Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors
摘要:
As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 mu M. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8 center dot H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.
Novel Imidazole-2-Benzamide Compounds Useful for the Treatment of Osteoarthritis
申请人:Kuklish Steven Lee
公开号:US20120157506A1
公开(公告)日:2012-06-21
The present invention provides compounds of the formula below
or pharmaceutical salts thereof, wherein R1, R2 and R3 are as described herein; methods of treating osteoarthritis using the compounds; and a process for preparing the compounds.
Imidazole-2-benzamide compounds useful for the treatment of osteoarthritis
申请人:Eli Lilly and Company
公开号:US08252831B2
公开(公告)日:2012-08-28
The present invention provides compounds of the formula below
or pharmaceutical salts thereof, wherein R1, R2 and R3 are as described herein; methods of treating osteoarthritis using the compounds; and a process for preparing the compounds.
Imidazole derivatives useful for the treatment of arthritis
申请人:Hughes Norman Earle
公开号:US08648200B2
公开(公告)日:2014-02-11
The present invention provides compounds of the formula below:
where A, X and R1-R6 are as described herein, a pharmaceutical salt thereof, and a pharmaceutical composition containing this compound; methods of treating pain associated with osteoarthritis using one of the compounds or a pharmaceutically acceptable salt thereof, and processes for preparing the compounds.