title: 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.
abstract: 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.
authors: Department of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. lawrence.hamann@bms.com
authors: David J
authors: DJ
authors: Augeri
authors: Jeffrey A
authors: JA
authors: Robl
authors: David A
authors: DA
authors: Betebenner
authors: David R
authors: DR
authors: Magnin
authors: Ashish
authors: A
authors: Khanna
authors: James G
authors: JG
authors: Robertson
authors: Aiying
authors: A
authors: Wang
authors: Ligaya M
authors: LM
authors: Simpkins
authors: Prakash
authors: P
authors: Taunk
authors: Qi
authors: Q
authors: Huang
authors: Song-Ping
authors: SP
authors: Han
authors: Benoni
authors: B
authors: Abboa-Offei
authors: Michael
authors: M
authors: Cap
authors: Li
authors: L
authors: Xin
authors: Li
authors: L
authors: Tao
authors: Effie
authors: E
authors: Tozzo
authors: Gustav E
authors: GE
authors: Welzel
authors: Donald M
authors: DM
authors: Egan
authors: Jovita
authors: J
authors: Marcinkeviciene
authors: Shu Y
authors: SY
authors: Chang
authors: Scott A
authors: SA
authors: Biller
authors: Mark S
authors: MS
authors: Kirby
authors: Rex A
authors: RA
authors: Parker
authors: Lawrence G
authors: LG
authors: Hamann
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D005951:Glucose Tolerance Test; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008862:Microsomes, Liver / Q000378:metabolism; D009570:Nitriles / Q000138:chemical synthesis / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D004151:Dipeptides; D007004:Hypoglycemic Agents; D007328:Insulin; D009570:Nitriles; D011480:Protease Inhibitors; D011392:Proline; C502994:saxagliptin; D018819:Dipeptidyl Peptidase 4; D000218:Adamantane; D005998:Glycine