Pyrazole-based factor Xa inhibitors containing N-arylpiperidinyl P4 residues

The synthesis, SAR, pharmacokinetic profile, and modeling studies of both monocyclic and fused pyrazoles containing substituted N-arylpiperidinyl P4 moieties that are potent and selective factor Xa inhibitors will be discussed. Fused pyrazole analog 16a, with a 2′-methylsulfonylphenyl piperidine P4...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 17; no. 5; pp. 1432 - 1437
Main Authors:	Qiao, Jennifer X., Cheng, Xuhong, Smallheer, Joanne M., Galemmo, Robert A., Drummond, Spencer, Pinto, Donald J.P., Cheney, Daniel L., He, Kan, Wong, Pancras C., Luettgen, Joseph M., Knabb, Robert M., Wexler, Ruth R., Lam, Patrick Y.S.
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 01-03-2007 Elsevier
Subjects:	Animals Biological and medical sciences Blood. Blood coagulation. Reticuloendothelial system Dogs Factor Xa Inhibitors Medical sciences Models, Molecular N-Arylpiperidine Pharmacology. Drug treatments Piperidines - administration & dosage Piperidines - chemical synthesis Piperidines - pharmacokinetics Protein Binding Pyrazole-based Pyrazoles - administration & dosage Pyrazoles - chemical synthesis Pyrazoles - pharmacokinetics SAR Structure-Activity Relationship Pyrazole-based SAR Factor Xa inhibitors N-Arylpiperidine Intravenous administration Molecular structure Sulfone Lactam Coagulation Factor Xa Anticoagulant Selectivity Modeling Structure activity relation Piperidine derivatives Antithrombotic agent Bicyclic compound Binding mode Pyrazole derivatives Chemical synthesis Dog Monocyclic compound Fissipedia Carnivora Serine endopeptidases Enzyme Oral administration Enzyme inhibitor X ray diffraction In vitro Peptidases In vivo W-Arylpiperidine Vertebrata Mammalia Animal Hydrolases Pharmacokinetics Crystalline structure
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Summary:	The synthesis, SAR, pharmacokinetic profile, and modeling studies of both monocyclic and fused pyrazoles containing substituted N-arylpiperidinyl P4 moieties that are potent and selective factor Xa inhibitors will be discussed. Fused pyrazole analog 16a, with a 2′-methylsulfonylphenyl piperidine P4 group, was shown to be the best compound in this series (FXa K i = 0.35 nM) based on potency, selectivity, and pharmacokinetic profile. The synthesis, SAR, pharmacokinetic profile, and modeling studies of both monocyclic and fused pyrazoles containing substituted N-arylpiperidinyl P4 moieties that are potent and selective factor Xa inhibitors will be discussed. Fused pyrazole analog 16a, with a 2′-methylsulfonylphenyl piperidine P4 group, was shown to be the best compound in this series (FXa K i = 0.35 nM) based on potency, selectivity, and pharmacokinetic profile.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2006.11.071