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.
Augeri
David J
DJ
Department of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. lawrence.hamann@bms.com
Robl
Jeffrey A
JA
Betebenner
David A
DA
Magnin
David R
DR
Khanna
Ashish
A
Robertson
James G
JG
Wang
Aiying
A
Simpkins
Ligaya M
LM
Taunk
Prakash
P
Huang
Qi
Q
Han
Song-Ping
SP
Abboa-Offei
Benoni
B
Cap
Michael
M
Xin
Li
L
Tao
Li
L
Tozzo
Effie
E
Welzel
Gustav E
GE
Egan
Donald M
DM
Marcinkeviciene
Jovita
J
Chang
Shu Y
SY
Biller
Scott A
SA
Kirby
Mark S
MS
Parker
Rex A
RA
Hamann
Lawrence G
LG
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
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