Seco-prolinenitrile inhibitors of dipeptidyl peptidase IV define minimal pharmacophore requirements at P1.
A series of seco-prolinenitrile-containing dipeptides were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV, a promising new target for treatment of type 2 diabetes. The inhibitors described herein assess the minimum structural requirements at P1 for this enzyme, resulting in the identification of inhibitors with low nM potency.
Magnin
David R
DR
Department of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA.
Taunk
Prakash C
PC
Robertson
James G
JG
Wang
Aiying
A
Marcinkeviciene
Jovita
J
Kirby
Mark S
MS
Hamann
Lawrence G
LG
D000243:Adenosine Deaminase / Q000737:chemistry*; D000814:Aniline Compounds / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006023:Glycoproteins / Q000737:chemistry*; D006801:Humans; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000737:chemistry*
D000814:Aniline Compounds; D004151:Dipeptides; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D009570:Nitriles; C008625:nitroaniline; D011392:Proline; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase