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Discovery of a First-in-Class Receptor Interacting Protein 2 (RIP2) Kinase Specific Clinical Candidate, 2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl Dihydrogen Phosphate, for the Treatment of Inflammatory Diseases.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-07-02 , DOI: 10.1021/acs.jmedchem.9b00575 Pamela A Haile 1 , Linda N Casillas 1 , Bartholomew J Votta 1 , Gren Z Wang 1 , Adam K Charnley 1 , Xiaoyang Dong 1 , Michael J Bury 1 , Joseph J Romano 1 , John F Mehlmann 1 , Bryan W King 1 , Karl F Erhard 1 , Charles R Hanning 1 , David B Lipshutz 1 , Biva M Desai 1 , Carol A Capriotti 1 , Michelle C Schaeffer 1 , Scott B Berger 1 , Mukesh K Mahajan 1 , Michael A Reilly 1 , Rakesh Nagilla 1 , Elizabeth J Rivera 1 , Helen H Sun 1 , John K Kenna 1 , Allison M Beal 1 , Michael T Ouellette 1 , Mike Kelly 2 , Gillian Stemp 2 , Máire A Convery 2 , Anna Vossenkämper 3 , Thomas T MacDonald 3 , Peter J Gough 1 , John Bertin 1 , Robert W Marquis 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-07-02 , DOI: 10.1021/acs.jmedchem.9b00575 Pamela A Haile 1 , Linda N Casillas 1 , Bartholomew J Votta 1 , Gren Z Wang 1 , Adam K Charnley 1 , Xiaoyang Dong 1 , Michael J Bury 1 , Joseph J Romano 1 , John F Mehlmann 1 , Bryan W King 1 , Karl F Erhard 1 , Charles R Hanning 1 , David B Lipshutz 1 , Biva M Desai 1 , Carol A Capriotti 1 , Michelle C Schaeffer 1 , Scott B Berger 1 , Mukesh K Mahajan 1 , Michael A Reilly 1 , Rakesh Nagilla 1 , Elizabeth J Rivera 1 , Helen H Sun 1 , John K Kenna 1 , Allison M Beal 1 , Michael T Ouellette 1 , Mike Kelly 2 , Gillian Stemp 2 , Máire A Convery 2 , Anna Vossenkämper 3 , Thomas T MacDonald 3 , Peter J Gough 1 , John Bertin 1 , Robert W Marquis 1
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RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.
中文翻译：
发现一流的受体相互作用蛋白2（RIP2）激酶特异性临床候选药物2-（（4-（苯并[d]噻唑-5-基氨基）-6-（叔丁基磺酰基）喹唑啉-7-基）氧基）磷酸二氢乙酯，用于治疗炎性疾病。
RIP2激酶已被确定为NOD2途径中的关键信号转导伙伴，可导致多种人类疾病，包括免疫介导的炎症性疾病。RIP2激酶的小分子抑制剂或其在NOD2途径上的信号伴侣，适合进入临床尚待描述。在此，我们报告了我们目前在1期临床研究中的前药临床化合物抑制剂3的发现和概况。化合物3以良好的激酶特异性与RIP2激酶有效结合，并在体内和人IBD外植体样品中具有出色的阻断许多促炎性细胞因子反应的活性。3的高度有利的理化和ADMET特性以及高效能导致了预期的人类低口服剂量。
更新日期：2019-07-02
中文翻译：
发现一流的受体相互作用蛋白2（RIP2）激酶特异性临床候选药物2-（（4-（苯并[d]噻唑-5-基氨基）-6-（叔丁基磺酰基）喹唑啉-7-基）氧基）磷酸二氢乙酯，用于治疗炎性疾病。
RIP2激酶已被确定为NOD2途径中的关键信号转导伙伴，可导致多种人类疾病，包括免疫介导的炎症性疾病。RIP2激酶的小分子抑制剂或其在NOD2途径上的信号伴侣，适合进入临床尚待描述。在此，我们报告了我们目前在1期临床研究中的前药临床化合物抑制剂3的发现和概况。化合物3以良好的激酶特异性与RIP2激酶有效结合，并在体内和人IBD外植体样品中具有出色的阻断许多促炎性细胞因子反应的活性。3的高度有利的理化和ADMET特性以及高效能导致了预期的人类低口服剂量。
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