Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2005-07, Vol.48 (15), p.5025-5037

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2005

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 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.