The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits

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• 作者：Sophie M. Bertrand ; Nicolas Ancellin ; Benjamin Beaufils ; Ryan P. Bingham ; Jennifer A. Borthwick ; Anne-B茅n茅dicte Boullay ; Eric Boursier ; Paul S. Carter ; Chun-wa Chung ; Ian Churcher ; Nerina Dodic ; Marie-H茅l猫ne Fouchet ; Charl猫ne Fournier ; Peter L. Francis ; Laura A. Gummer ; Kenny Herry ; Andrew Hobbs ; Clare I. Hobbs ; Paul Homes ; Craig Jamieson ; Edwige Nicodeme ; Stephen D. Pickett ; Iain H. Reid ; Graham L. Simpson ; Lisa A. Sloan ; Sarah E. Smith ; Donald O鈥橬. Somers ; Claus Spitzfaden ; Colin J. Suckling ; Klara Valko ; Yoshiaki Washio ; Robert J. Young
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 24, 2015
• 年：2015
• 卷：58
• 期：18
• 页码：7140-7163
• 全文大小：1049K
• ISSN：1520-4804

文摘

The hybridization of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm) based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimization of potency with maintenance of ligand efficiency, while the focus on physicochemical properties delivered compounds with excellent pharmacokinetic exposure that enabled a proof of concept experiment in mice. Oral administration of 2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile 61 significantly raised the circulating levels of the branched-chain amino acids leucine, isoleucine, and valine in this acute study.