Nakajima Katsumasa, April Myriam, Brewer Jason T, Daniels Thomas, Forster Cornelia J, Gilmore Thomas A, Jain Monish, Kanter Aaron, Kwak Youngshin, Li Jingzhou, McQuire Les, Serrano-Wu Michael H, Streeper Ryan, Szklennik Paul, Thompson James, Wang Bing
Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
Cardiovascular and Metabolism, Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
Bioorg Med Chem Lett. 2016 Feb 15;26(4):1245-8. doi: 10.1016/j.bmcl.2016.01.025. Epub 2016 Jan 11.
Diamide compounds were identified as potent DGAT1 inhibitors in vitro, but their poor molecular properties resulted in low oral bioavailability, both systemically and to DGAT1 in the enterocytes of the small intestine, resulting in a lack of efficacy in vivo. Replacing an N-alkyl group on the diamide with an N-aryl group was found to be an effective strategy to confer oral bioavailability and oral efficacy in this lipophilic diamide class of inhibitors.
二酰胺化合物在体外被鉴定为有效的二酰甘油酰基转移酶1（DGAT1）抑制剂，但其较差的分子性质导致口服生物利用度较低，无论是在全身还是在小肠肠细胞中的DGAT1，从而导致体内缺乏疗效。发现用N-芳基取代二酰胺上的N-烷基是赋予这类亲脂性二酰胺抑制剂口服生物利用度和口服疗效的有效策略。
