Discovery of non-covalent dipeptidyl peptidase IV inhibitors which induce a conformational change in the active site

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 6, 2007, Pages 1765-1768

  Sheehan, Scott M ^a   Mest, Hans Juergen ^a   Watson, Brian M ^a   Klimkowski, Valentine J ^a   Timm, David E ^a   Cauvin, Annick ^b   Parsons, Stephen H ^a   Shi, Qing ^a   Canada, Emily J ^a   Wiley, Michael R ^a   Ruehter, Gerd ^a   Evers, Britta ^a   Petersen, Soenke ^a   Blaszczak, Larry C ^a   Pulley, Shon R ^a   Margolis, Brandon J ^a   Wishart, Graham N ^a   Renson, Beatrice ^b   Hankotius, Dirk ^a   Mohr, Michael ^a   Zechel, Johann Christian ^a   Michael Kalbfleisch, J ^a   Dingess Hammond, Elizabeth A ^a   Boelke, Andre ^a   Weichert, Andreas G ^a   more..

^a ELI LILLY AND COMPANY   (United States)

^b Eli Lilly Benelux   (Belgium)

Author keywords

Dipeptidyl peptidase IV; Oral glucose tolerance test; Protease inhibitor; X ray co crystal structure

Indexed keywords

DIPEPTIDYL PEPTIDASE IV INHIBITOR; GLUCOSE; INSULIN; TYROSINE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; COVALENT BOND; CRYSTALLIZATION; ENZYME ACTIVE SITE; ENZYME INHIBITION; GLUCOSE TOLERANCE TEST; HYDROGEN BOND; HYPOGLYCEMIA; NONHUMAN; ORAL GLUCOSE TOLERANCE TEST; RAT; ROTATION; X RAY ANALYSIS;

ANIMALS; BINDING SITES; COMPUTER SIMULATION; CRYSTALLOGRAPHY, X-RAY; DIPEPTIDYL PEPTIDASE 4; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; DRUG EVALUATION, PRECLINICAL; HYDROGEN BONDING; MALE; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PROTEASE INHIBITORS; RATS; RATS, WISTAR; SPECTROMETRY, FLUORESCENCE;

EID: 33847021133     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.12.074     Document Type: Article

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20. Energy minimization of the X-ray bound and linear conformations of 1 was performed with CHARMm (QUANTA2005, Accelrys Software Inc.) using no non-bond cutoffs, a distance dependent dielectric, and a 3.0 dielectric constant. Conformational energy differences (linear-U-shaped) were found to be 3.6 (CHARMm) and 2.8 (MMFF) kcal/mol for each force field, respectively.
21. (a) Coordinates for structure 1 have been deposited with the RCSB protein databank. PDB deposition #20GZ; (b) DPPIV crystals were grown in the presence of compounds 1, 11, and 12 using methods described by Rasmussen, H. B.; Branner, S.; Wiberg, F. C.; Wagtman, N. R. Nat. Struct. Biol., 2003, 10, 19. Diffraction data were collected at 100 K at the Advanced Photon Source sector 17 (IMCA-CAT). Structures of DPPIV complexed with compounds 1, 11, and 12 were solved using models initially derived from 1N1M.pdb and were refined to resolutions of 2.1, 2.0, and 2.3 Å, respectively.
22. 2O [M+H] 311.1515; found: 311.1553.
23. 2 [M+H] 329.1621; found: 329.1660.
24. We have found that the majority of the DPP-IV activity results from a single enantiomer (unpublished results) and as such occasionally racemates are tested for expedience.
25. NAr reaction of the corresponding commercially available amino alcohol with 4-fluorobenzonitrile following the procedure of Vogler, M.; Koert, U.; Harms, K.; Dorsch, D.; Gleitz, J.; Raddatz, P. Synthesis, 2004, 8, 1211.
26. OGTT experiment: the compound was administered orally to fasted male Wistar rats (n = 6) 10 min before a glucose load of 2.5 g/kg. Blood samples were collected from the tail tip over 120 min for the determination of glucose (hexokinase method), insulin (immunoassay from CrystalChem Inc., ref. INSKR20), and DPP-IV activity (fluorimetric endpoint assay using Gly-Pro-AMC (Bachem I-1225) as substrate and AMC (Bachem Q-1025) for calibration).
27. Compound 12 was found to have >10,000× selectivity over dipeptidyl peptidases 8 and 9.