4A5S

CRYSTAL STRUCTURE OF HUMAN DPP4 IN COMPLEX WITH A NOVAL HETEROCYCLIC DPP4 INHIBITOR

Summary for 4A5S

• Entry DOI: 10.2210/pdb4a5s/pdb
• Related: 1J2E 1N1M 1NU6 1NU8 1PFQ 1R9M 1R9N 1RWQ 1TK3 1TKR 1U8E 1W1I 1WCY 1X70 2AJL 2BGN 2BGR 2BUB 2G5P 2G5T 2G63 2JID
• Descriptor: DIPEPTIDYL PEPTIDASE 4 SOLUBLE FORM, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 6-[(3S)-3-AMINOPIPERIDIN-1-YL]-5-BENZYL-4-OXO-3-(QUINOLIN-4-YLMETHYL)-4,5-DIHYDRO-3H-PYRROLO[3,2-D]PYRIMIDINE-7-CARBONITRILE, ... (6 entities in total)
• Functional Keywords: hydrolase, type 2 diabetes, novartis compound nvp-biv988
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 176783.15

Authors

Ostermann, N.,Kroemer, M.,Zink, F.,Gerhartz, B.,Sutton, J.M.,Clark, D.E.,Dunsdon, S.J.,Fenton, G.,Fillmore, A.,Harris, N.V.,Higgs, C.,Hurley, C.A.,Krintel, S.L.,MacKenzie, R.E.,Duttaroy, A.,Gangl, E.,Maniara, W.,Sedrani, R.,Namoto, K.,Sirockin, F.,Trappe, J.,Hassiepen, U.,Baeschlin, D.K. (deposition date: 2011-10-28, release date: 2012-02-08, Last modification date: 2024-11-20)

Primary citation

Sutton, J.M.,Clark, D.E.,Dunsdon, S.J.,Fenton, G.,Fillmore, A.,Harris, N.V.,Higgs, C.,Hurley, C.A.,Krintel, S.L.,Mackenzie, R.E.,Duttaroy, A.,Gangl, E.,Maniara, W.,Sedrani, R.,Namoto, K.,Ostermann, N.,Gerhartz, B.,Sirockin, F.,Trappe, J.,Hassiepen, U.,Baeschlin, D.K.
Novel Heterocyclic Dpp-4 Inhibitors for the Treatment of Type 2 Diabetes.
Bioorg.Med.Chem.Lett., 22:1464-, 2012

PubMed Abstract: Novel deazaxanthine-based DPP-4 inhibitors have been identified that are potent (IC(50) <10nM) and highly selective versus other dipeptidyl peptidases. Their synthesis and SAR are reported, along with initial efforts to improve the PK profile through decoration of the deazaxanthine core. Optimisation of compound 3a resulted in the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were possible by changing from the deazahypoxanthine to the deazaxanthine template, culminating in compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rat, suggestive of once daily dosing in man.

PubMed: 22177783
DOI: 10.1016/J.BMCL.2011.11.054

Experimental method

X-RAY DIFFRACTION (1.62 Å)