Design, synthesis, and biological evaluation of a series of piperazine ureas as fatty acid amide hydrolase inhibitors
BIOORGANIC & MEDICINAL CHEMISTRY
Authors: Kono, Mitsunori; Matsumoto, Takahiro; Imaeda, Toshihiro; Kawamura, Toru; Fujimoto, Shinji; Kosugi, Yohei; Odani, Tomoyuki; Shimizu, Yuji; Matsui, Hideki; Shimojo, Masato; Kori, Masakuni
Abstract
A series of piperazine ureas were designed, synthesized, and evaluated for their potential as novel orally efficacious fatty acid amide hydrolase (FAAH) inhibitors for the treatment of neuropathic and inflammatory pain. We carried out an optimization study of compound 5 to improve its in vitro FAAH inhibitory activity, and identified the 2-pyrimidinylpiperazine derivative 21d with potent inhibitory activity, favorable DMPK profile and brain permeability. Compound 21d showed robust and dose-dependent analgesic efficacy in animal models of both neuropathic and inflammatory pain. (C) 2014 Published by Elsevier Ltd.
True or false? Challenges and recent highlights in the development of aspirin prodrugs
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Authors: Willetts, Steffan; Foley, David W.
Abstract
Aspirin is a widely used medicine for a variety of indications. It is unique amongst non-steroidal anti-inflammatory drugs (NSAIDs) in that it causes irreversible acetylation of COX enzymes. Like all NSAIDs however, aspirin causes severe gastrointestinal side-effects, in particular with chronic administration. Prodrugs of aspirin have been proposed as a solution to these side-effects. However, identifying true prodrugs of aspirin, rather than salicylic acid, has proven challenging. This review details the challenges and highlights recent progress in the development of such prodrugs. (c) 2020 Elsevier Masson SAS. All rights reserved.
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