Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38¦Á inhibitor

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• 作者：Chunjian Liu ; ^{chunjian.liu@bms.com} ; James Lin ; Gerry Everlof ; Christoph Gesenberg ; Hongjian Zhang ; Punit H. Marathe ; Mary Malley ; Michael A. Galella ; Murray Mckinnon ; John H. Dodd ; Joel C. Barrish ; Gary L. Schieven ; Katerina Leftheris
• 关键词：Prodrugs ; Carbamoylmethylene linked prodrugs ; Prodrugs of secondary amides
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：15 May, 2013
• 年：2013
• 卷：23
• 期：10
• 页码：3028-3033
• 全文大小：557 K

文摘

A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38¦Á inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and ¦Á-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2 mpk (equivalent to 10 mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10 mpk of 1 itself. At a suspension dose of 142 mpk (equivalent to 100 mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates.