2I03

Crystal structure of human dipeptidyl peptidase 4 (DPP IV) with potent alkynyl cyanopyrrolidine (ABT-279)

Summary for 2I03

• Entry DOI: 10.2210/pdb2i03/pdb
• Related: 2G5P 2G5T 2G63
• Descriptor: Dipeptidyl peptidase 4, 2-[4-({2-[(2S,5R)-2-(AMINOMETHYL)-5-ETHYNYLPYRROLIDIN-1-YL]-2-OXOETHYL}AMINO)-4-METHYLPIPERIDIN-1-YL]ISONICOTINIC ACID (3 entities in total)
• Functional Keywords: enzyme, serine peptidase, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Dipeptidyl peptidase 4 soluble form: Secreted . Cell membrane ; Single- pass type II membrane protein: P27487
• Total number of polymer chains: 4
• Total formula weight: 337408.83

Authors

Longenecker, K.L.,Madar, D.J. (deposition date: 2006-08-09, release date: 2006-12-12, Last modification date: 2024-11-13)

Primary citation

Madar, D.J.,Kopecka, H.,Pireh, D.,Yong, H.,Pei, Z.,Li, X.,Wiedeman, P.E.,Djuric, S.W.,Von Geldern, T.W.,Fickes, M.G.,Bhagavatula, L.,McDermott, T.,Wittenberger, S.,Richards, S.J.,Longenecker, K.L.,Stewart, K.D.,Lubben, T.H.,Ballaron, S.J.,Stashko, M.A.,Long, M.A.,Wells, H.,Zinker, B.A.,Mika, A.K.,Beno, D.W.,Kempf-Grote, A.J.,Polakowski, J.,Segreti, J.,Reinhart, G.A.,Fryer, R.M.,Sham, H.L.,Trevillyan, J.M.
Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.
J.Med.Chem., 49:6416-6420, 2006

PubMed Abstract: Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.

PubMed: 17034148
DOI: 10.1021/jm060777o

Experimental method

X-RAY DIFFRACTION (2.4 Å)