沙格列汀（BMS-477118）的发现及临床前研究概况：一种用于治疗2型糖尿病的高效、长效、口服活性二肽基肽酶IV抑制剂

Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

作者信息

Augeri David J, Robl Jeffrey A, Betebenner David A, Magnin David R, Khanna Ashish, Robertson James G, Wang Aiying, Simpkins Ligaya M, Taunk Prakash, Huang Qi, Han Song-Ping, Abboa-Offei Benoni, Cap Michael, Xin Li, Tao Li, Tozzo Effie, Welzel Gustav E, Egan Donald M, Marcinkeviciene Jovita, Chang Shu Y, Biller Scott A, Kirby Mark S, Parker Rex A, Hamann Lawrence G

机构信息

Department of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA.

出版信息

J Med Chem. 2005 Jul 28;48(15):5025-37. doi: 10.1021/jm050261p.

DOI:10.1021/jm050261p

PMID:16033281

Abstract

Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.

摘要

为了进一步阐明我们之前公开的一系列β-季铵氨基酸连接的L-顺式-4,5-亚甲基脯氨酸腈二肽基肽酶IV（DPP-IV）抑制剂的构效关系（SAR），我们对α-环烷基取代甘氨酸的β位进行乙烯基取代研究。尽管全身暴露性较差，但乙烯基取代的化合物在急性大鼠离体血浆DPP-IV抑制模型中显示出延长的作用持续时间。制备了氧化的推定代谢物，并在测量Zucker（fa/fa）大鼠葡萄糖清除率的功效模型中显示出其前体的效力和延长的作用持续时间。将这种方法扩展到金刚烷基甘氨酸衍生的抑制剂，导致发现了高效抑制剂，包括羟基金刚烷基化合物BMS-477118（沙格列汀），一种高效、稳定且长效的DPP-IV抑制剂，目前正在进行治疗2型糖尿病的临床试验。