905833-50-3Relevant academic research and scientific papers
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
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.
, p. 5025 - 5037 (2007/10/03)
Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of β-quaternary amino acid linked L-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the β-position of α-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 Zuckerfa/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.
