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.

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.

Citation

David J Augeri, Jeffrey A Robl, David A Betebenner, David R Magnin, Ashish Khanna, James G Robertson, Aiying Wang, Ligaya M Simpkins, Prakash Taunk, Qi Huang, Song-Ping Han, Benoni Abboa-Offei, Michael Cap, Li Xin, Li Tao, Effie Tozzo, Gustav E Welzel, Donald M Egan, Jovita Marcinkeviciene, Shu Y Chang, Scott A Biller, Mark S Kirby, Rex A Parker, Lawrence G Hamann. 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. Journal of medicinal chemistry. 2005 Jul 28;48(15):5025-37

Mesh Tags

Substances

PMID: 16033281

search → result