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
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
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DOI：
10.1021/jm050261p
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发表时间：
2005-07-28
影响因子：
7.3
通讯作者：
Hamann, LG
中科院分区：
文献类型：
--
作者：
Augeri, DJ;Robl, JA;Hamann, LG
在我们先前公开的一系列β-季氨基酸连接的L-顺式-4，5-甲酰基脯氨腈二肽基肽酶IV（DPP-IV）抑制剂中进一步阐明结构-活性关系（SAR）的努力导致了对α-环烷基取代的甘氨酸的β-位置处的乙烯基取代的研究。尽管全身暴露较差，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Zucker（fa/fa）大鼠中测定葡萄糖清除率的有效性模型中显示出其前体的效力和延长的作用持续时间。将该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、稳定和长效的DPP-IV抑制剂，目前正在进行治疗2型糖尿病的临床试验。
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.