title: 1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties.
abstract: Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. The synthesis and structure-activity relationship of a new DPP-IV inhibitor class, N-substituted-glycyl-2-cyanopyrrolidines, are described as well as the path that led from clinical development compound 1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728, 8c) to its follow-up, 1-[[(3-hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP-LAF237, 12j). The pharmacological profile of 12j in obese Zucker fa/fa rats along with pharmacokinetic profile comparison of 8c and 12j in normal cynomolgus monkeys is discussed. The results suggest that 12j is a potent, stable, selective DPP-IV inhibitor possessing excellent oral bioavailability and potent antihyperglycemic activity with potential for once-a-day administration.
authors.affiliation: Novartis Institute for Biomedical Research, One Health Plaza, East Hanover, New Jersey 07936, USA. edwin.villhauer@pharma.novartis.com
authors.forename: Edwin B
authors.initials: EB
authors.lastname: Villhauer
authors.forename: John A
authors.initials: JA
authors.lastname: Brinkman
authors.forename: Goli B
authors.initials: GB
authors.lastname: Naderi
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Burkey
authors.forename: Beth E
authors.initials: BE
authors.lastname: Dunning
authors.forename: Kapa
authors.initials: K
authors.lastname: Prasad
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Mangold
authors.forename: Mary E
authors.initials: ME
authors.lastname: Russell
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hughes
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000032:analysis; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D013329:Structure-Activity Relationship
chemical_list: C475520:1-(((3-hydroxy-1-adamantyl)amino)acetyl)-2-cyanopyrrolidine; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4; D000218:Adamantane