Discovery, SAR, and X-ray structure of novel biaryl-based dipeptidyl peptidase IV inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 1, 2006, Pages 123-128

  Qiao, Lei ^a   Baumann, Christian A ^a   Crysler, Carl S ^a   Ninan, Nisha S ^a   Abad, Marta C ^a   Spurlino, John C ^a   Desjarlais, Renee L ^a   Kervinen, Jukka ^a   Neeper, Mike P ^a   Bayoumy, Shariff S ^a   Williams, Robyn ^a   Deckman, Ingrid C ^a   Dasgupta, Malini ^a   Reed, Rolanda L ^a   Huebert, Norman D ^a   Tomczuk, Bruce E ^a   Moriarty, Kevin J ^a  

^a JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

Dipeptidyl peptidase IV Inhibitors; SAR; X ray structure

Indexed keywords

DIPEPTIDYL PEPTIDASE IV INHIBITOR; PYRROLIDINE DERIVATIVE; THIAZOLIDINE DERIVATIVE;

ARTICLE; CELL MEMBRANE PERMEABILITY; CELL STRAIN CACO 2; CONTROLLED STUDY; DRUG DESIGN; DRUG STRUCTURE; ENZYME ACTIVE SITE; ENZYME BINDING; ENZYME INHIBITION; HUMAN; HUMAN CELL; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS; X RAY CRYSTALLOGRAPHY;

ANIMALS; ANTIGENS, CD26; ANTINEOPLASTIC AGENTS; BINDING SITES; BLOOD GLUCOSE; CACO-2 CELLS; CHEMISTRY, PHARMACEUTICAL; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; DRUG SCREENING ASSAYS, ANTITUMOR; ENZYME INHIBITORS; HUMANS; KINETICS; MICE; MODELS, CHEMICAL; MODELS, MOLECULAR; PROTEASE INHIBITORS; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 27744520270     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.09.037     Document Type: Article

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36. (a) PDB code is 2AJL.
37. 4 gradient in 20 mM Tris-HCl, pH 8.0). Purified DPP IV (0.5 mg/mL) was dialyzed against 20 mM Tris-HCl, pH 8.0, 25 mM NaCl, flash-frozen in liquid nitrogen, and stored at -80°C for enzyme assays. For crystallographic purposes, DPP IV was concentrated to 18 mg/mL by filtration (Ultracel-4, 30000 MWCO, Millipore) after dialysis.
38. 1 space group, with unit cell parameters a = 65.28, b = 126.88, c = 110.83 Å, and β = 99.4°. The structure was determined and refined by molecular replacement with CNX (Brunger, A. T.; Adams, P. D.; Clore, G. M.; DeLano, W. L.; Gros, P.; Grosse-Kunstleve, R. W.; Jiang, J. S.; Kuszewski, J., Nilges, M.; Pannu, N. S.; Read, R. J., Rice, L. M.; Simonson, T.; Warren, G. L. Acta Crystallogr. 1998, D54, 905) using the structure of DPP IV with valine-pyrrolidide as a search model (PDB ID: 1NIM).
39. All model building was done using O (Jones, T. A.; Zou, J. Y.; Cowan, S. W.; Kjeldgaard, M. Acta Crystallogr. 1991, A47, 110). The final structure was refined to an R-factor of 22.6.
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