2OAG
Crystal structure of human dipeptidyl peptidase IV (DPPIV) with pyrrolidine-constrained phenethylamine 29g
Summary for 2OAG
| Entry DOI | 10.2210/pdb2oag/pdb |
| Descriptor | Dipeptidyl peptidase 4, (3R,4S)-1-{6-[3-(METHYLSULFONYL)PHENYL]PYRIMIDIN-4-YL}-4-(2,4,5-TRIFLUOROPHENYL)PYRROLIDIN-3-AMINE (3 entities in total) |
| Functional Keywords | serine-peptidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| 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 | 337457.80 |
| Authors | Backes, B.J.,Longenecker, K.L.,Hamilton, G.L.,Stewart, K.D.,Lai, C.,Kopecka, H. (deposition date: 2006-12-15, release date: 2007-09-11, Last modification date: 2024-11-06) |
| Primary citation | Backes, B.J.,Longenecker, K.,Hamilton, G.L.,Stewart, K.,Lai, C.,Kopecka, H.,von Geldern, T.W.,Madar, D.J.,Pei, Z.,Lubben, T.H.,Zinker, B.A.,Tian, Z.,Ballaron, S.J.,Stashko, M.A.,Mika, A.K.,Beno, D.W.,Kempf-Grote, A.J.,Black-Schaefer, C.,Sham, H.L.,Trevillyan, J.M. Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit. Bioorg.Med.Chem.Lett., 17:2005-2012, 2007 Cited by PubMed Abstract: A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal. PubMed: 17276063DOI: 10.1016/j.bmcl.2007.01.026 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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