Generation of a new class of hNK2 receptor ligands using the 'fragment approach'

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 3, 2005, Pages 585-588

  D'Andrea, Piero ^a   Porcelloni, Marina ^a   Madami, Andrea ^a   Patacchini, Riccardo ^a   Altamura, Maria ^a   Fattori, Daniela ^a  

^a Menarini Ricerche SpA   (Italy)

Author keywords

Fragment approach; NK2

Indexed keywords

NATURAL KILLER CELL RECEPTOR NKG2D; NEPADUTANT; RECEPTOR BLOCKING AGENT; SAREDUTANT; UK 224671; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL BOND; CLINICAL TRIAL; DRUG STRUCTURE; FRAGMENTATION REACTION; HUMAN; PROTEIN CONFORMATION; STRUCTURE ANALYSIS;

AMIDES; DRUG DESIGN; HUMANS; LIGANDS; MODELS, MOLECULAR; RECEPTORS, NEUROKININ-1; RECEPTORS, NEUROKININ-2; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

EID: 12444321923     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.11.045     Document Type: Article

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11. 1H NMR and MS purity, evaluated by analytical HPLC (214 nm), was >95%
12. i
13. B = log[dose ratio - 1] - log [antagonist concentration]
14. ACD/Labs 7.0 (Advanced Chemistry Development Inc.)
15. The conformational analyses were carried out using the grid search module of Sybyl 6.91 (Tripos Inc.). The resulting conformers were minimized in Sybyl using the MMFF94s force field with a water dielectric constant of 78.5. Structures located more than 3 kcal/mol above the minimum were discarded
16. A. Poulsen, B. Bjørnholm, K. Gundertofte, I.D. Pogozheva, and T. Liljefors J. Comput.-Aided Mol. Des. 17 2003 765 783
17. The computational study of MEN 14933 was performed using MacroModel 8.5 (Schröedinger, L. L. C.). The conformational space was searched using the Monte Carlo method (5555 steps). All rotable single bonds and the flexible morpholine ring were included in the search. The energy minimizations were performed using the MMFF94s force field with the GB/SA solvation model. Conformations (337) within 3 kcal/mol of the minimum, were obtained