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Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors.

Vincent Mascitti, Tristan S Maurer, Ralph P Robinson, Jianwei Bian, Carine M Boustany-Kari, Thomas Brandt, Benjamin M Collman, Amit S Kalgutkar, Michelle K Klenotic, Michael T Leininger, André Lowe, Robert J Maguire, Victoria M Masterson, Zhuang Miao, Emi 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, and Tong Zhu

J Med Chem 54(8):2952-60 (2011) PMID 21449606

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.

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