Discovery of a Clinical Candidate from the Structurally Unique Dioxa-bicyclo[3.2.1]octane Class of Sodium-Dependent Glucose Cotransporter 2 Inhibitors

作者：Vincent Mascitti, Tristan S. Maurer, Ralph P. Robinson, Jianwei Bian, Carine M. Boustany‐Kari, Thomas A. Brandt, Benjamin M. Collman, Amit S. Kalgutkar, M.K. Klenotic, Michael T. Leininger, André Lowe, Robert J. Maguire, Victoria M. Masterson, Zhuang Miao, E. Mukaiyama, Jigna D. Patel, John C. Pettersen, Cathy Préville, Brian Samas, Li She, Zhanna Sobol, Claire M. Steppan, Benjamin D. Stevens, Benjamin A. Thuma, Meera Tugnait, Dongxiang Zeng, Tong Zhu · 发表于：Journal of Medicinal Chemistry · 年份：2011 · DOI：10.1021/jm200049r · 被引用次数：134 · 研究领域：Diabetes Treatment and Management、Metabolism, Diabetes, and Cancer、Pancreatic function and diabetes

Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.