Novel and potent NPY5 receptor antagonists derived from virtual screening and iterative parallel chemistry design

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 6, 2005, Pages 1599-1603

  Guba, Wolfgang ^a   Neidhart, Werner ^a   Nettekoven, Matthias ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

Lead generation; Parallel chemistry; Pharmacophores; Virtual screening

Indexed keywords

ANTIOBESITY AGENT; NEUROPEPTIDE Y RECEPTOR ANTAGONIST; NEUROPEPTIDE Y5 RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG;

ARTICLE; DRUG DESIGN; DRUG DETERMINATION; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; ELECTRON TRANSPORT; HYDROPHOBICITY; REACTION OPTIMIZATION; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS; VIRTUAL REALITY;

EID: 14644418990     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.01.063     Document Type: Article

References (11)

1. K. Tatemoto, M. Carlquist, and V. Mutt Nature (London, United Kingdom) 296 1982 659 661
2. M.C. Michel, A. Beck-Sickinger, H. Cox, H.N. Doods, H. Herzog, D. Larhammar, R. Quirion, T. Schwartz, and T. Westfall Pharmacol. Rev. 50 1998 143 150
3. L. Criscione, P. Rigollier, C. Batzl-Hartmann, H. Rueger, A. Stricker-Krongrad, P. Wyss, L. Brunner, S. Whitebread, Y. Yamaguchi, C. Gerald, R.O. Heurich, M.W. Walker, M. Chiesi, W. Schilling, K.G. Hofbauer, and N. Levens J. Clin. Invest. 102 1998 2136 2145
4. Daylight Chemical Information Systems, Inc., http://www.daylight.com, 2002
5. Fukami, T.; Okamoto, O.; Fukuroda, T.; Kanatani, A.; Ihara M. PCT Int. Appl. WO 9840356 (Banyu Pharmaceutical Co., Ltd., Japan) 1998, 78
6. Norman, M. H.; Chen, N.; Han, N.; Liu, L.; Hurt, C. R.; Fotsch, C. H.; Jenkins, T. J.; Moreno O. A. PCT Int. Appl. WO9940091, (Amgen Inc., USA). 1999, 469
7. Breu, V.; Dautzenberg, F.; Guerry, P.; Nettekoven, M. H.; Pflieger P. PCT Int. Appl. WO2002020488, (F. Hoffmann-La Roche A.-G., Switz.). 2002, 62
8. Catalyst, version 4.7; Accelrys, Inc.: San Diego, 2002
9. Y.-I. Lin, C.M. Seifert, S.M. Kang, J.P. Dusza, and S.A. Lang Jr. J. Heterocycl. Chem. 16 1979 1377 1383
10. General experimental procedure for the synthesis of 9: A mixture of aryl thiourea (1 mmol) and N,N-dimethylformamide dimethyl acetal (1 ml) was heated to 100°C for 1 h. The precipitate was filtered off, washed with THF and dried to obtain the respective 1-dimethylaminomethylene-aryl-thiourea. When no precipitation occurred the mixture was evaporated to dryness and the residue was suspended in DCM, filtered and dried to yield the title compound. Then a solution of 1-dimethylaminomethylene-aryl-thiourea (0.13 mmol) in DMF (0.33 ml) was added α-bromoketone (0.13 mmol) and the mixture was allowed to stir at room temperature for 16 h. Then N,N-diisopropylethylamine (0.13 mmol) was added and the mixture was subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient to yield the title compound after evaporation of the product fractions. The structural identity of the compounds was corroborated by LC-MS and NMR
11. General experimental procedure for the synthesis of α-bromoketones: To a solution of aryl-ethanone (40 mmol) in HBr (33%, 21 ml) and methanol (7 ml) was added bromine (40 mmol) and the mixture was heated to 60°C for 3 h. After removal of the volatiles under reduced pressure the residue was washed with diethyl ether and ethyl acetate to obtain the title compound which could be optionally further purified. For a more detailed description of workflow procedures utilised in the preparation of compound arrays please refer to: M. Nettekoven, and A.W. Thomas Curr. Med. Chem. 9 2002 2179 2190