Discovery of novel isothiazole inhibitors of the TrkA kinase: structure-activity relationship, computer modeling, optimization, and identification of highly potent antagonists

Bioorganic & Medicinal Chemistry Letters
Blaise LippaMatthew D Wessel

Abstract

The design, synthesis, and biological evaluation of potent inhibitors of the TrkA kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.

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Citations

Mar 29, 2014·Bioorganic & Medicinal Chemistry Letters·Andrew M HaidleJonathan R Young
Nov 3, 2010·Journal of Molecular Graphics & Modelling·Crtomir PodlipnikPierfausto Seneci
Apr 23, 2013·Chemical Biology & Drug Design·Andrei LeitãoAngelika Eggert
Feb 27, 2009·The Biochemical Journal·Tracy ChenPaul Bauer
Aug 13, 2010·Cancer Biology & Therapy·Turker YilmazMichael E Kupferman
Aug 21, 2012·Journal of Molecular Biology·T BertrandM Mathieu
Dec 7, 2007·Bioorganic & Medicinal Chemistry Letters·Soong-Hoon KimPing Chen
Nov 13, 2008·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Judy J WatsonDavid Dawbarn
May 16, 2009·Expert Opinion on Therapeutic Patents·Tao WangMichelle L Lamb
Apr 4, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Melanie AbramMichael Zemlin
Jan 1, 2012·International Journal of Medicinal Chemistry·Stéphane L RaeppelArkadii Vaisburg
Mar 2, 2021·Acta Pharmaceutica Sinica. B·Tingting JiangLiang Ouyang
Jul 24, 2008·Journal of Medicinal Chemistry·Tao WangDingwei Yu
Dec 17, 2011·The Journal of Organic Chemistry·Andriy V TymtsunikIgor V Komarov
Dec 1, 2020·The Journal of Organic Chemistry·Zhu-Zhu ZhangXing-Guo Zhang

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