Design, Synthesis, and Evaluation of 2-Methyl- and 2-Amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines as Ring-Constrained 2-Anilino-4-(thiazol-5-yl)pyrimidine Cyclin-Dependent

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• 作者：Neil A. McIntyre ; Campbell McInnes ; Gary Griffiths ; Anna L. Barnett ; George Kontopidis ; Alexandra M. Z. Slawin ; Wayne Jackson ; Mark Thomas ; Daniella I. Zheleva ; Shudong Wang ; David G. Blake ; Nicholas
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：March 11, 2010
• 年：2010
• 卷：53
• 期：5
• 页码：2136-2145
• 全文大小：971K
• 年卷期：v.53,no.5(March 11, 2010)
• ISSN：1520-4804

文摘

Following the recent discovery and development of 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin dependent kinase (CDK) inhibitors, a program was initiated to evaluate related ring-constrained analogues, specifically, 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines for inhibition of CDKs. Here we report the rational design, synthesis, structure−activity relationships (SARs), and cellular mode-of-action profile of these second generation CDK inhibitors. Many of the analogues from this chemical series inhibit CDKs with very low nanomolar K_i values. The most potent compound reported in this study inhibits CDK2 with an IC₅₀ of 0.7 nM ([ATP] = 100 μM). Furthermore, an X-ray crystal structure of 2-methyl-N-(3-(nitro)phenyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amine (11g), a representative from the chemical series in complex with cyclin A−CDK2, is reported, confirming the design rationale and expected binding mode within the CDK2 ATP binding pocket.