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1.
J Pharmacol Exp Ther ; 333(3): 707-16, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20228155

ABSTRACT

Rho kinase, is the most widely studied downstream effector of the small Rho GTPase RhoA. Two Rho kinase isoforms have been described and are frequently referred to in the literature as ROCK1 and ROCK2. The RhoA-Rho kinase pathway has been implicated in the recruitment of cellular infiltrates to disease loci in a number of preclinical animal models of inflammatory disease. In this study, we used biochemical enzyme assays and a cellular target biomarker assay to define PF-4950834 [N-methyl-3-{[(4-pyridin-4-ylbenzoyl)amino]methyl}benzamide] as an ATP-competitive, selective Rho kinase inhibitor. We further used PF-4950834 to study the role of Rho kinase activation in lymphocyte and neutrophil migration in addition to the endothelial cell-mediated expression of adhesion molecules and chemokines, which are essential for leukocyte recruitment. The inhibitor blocked stromal cell-derived factor-1alpha-mediated chemotaxis of T lymphocytes in vitro and the synthesis of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in activated human endothelial cells in vitro. The secretion of chemokines interleukin-8 and monocyte chemoattractant protein-1 was also inhibited in activated endothelial cells. In addition, when dosed orally, the compound potently inhibited neutrophil migration in a carrageenan-induced acute inflammation model. In summary, we have used a pharmacologic approach to link Rho kinase activation to multiple phenotypes that can contribute to leukocyte infiltration. Inhibition of this pathway therefore could be strongly anti-inflammatory and provide therapeutic benefit in chronic inflammatory diseases.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal , Benzamides/pharmacology , Protein Kinase Inhibitors/pharmacology , rho-Associated Kinases/antagonists & inhibitors , Animals , Benzamides/pharmacokinetics , Biological Availability , Blotting, Western , Cell Adhesion Molecules/biosynthesis , Cell Movement/drug effects , Chemokines/biosynthesis , Dose-Response Relationship, Drug , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Flow Cytometry , Humans , Inflammation/chemically induced , Inflammation/prevention & control , Interleukin-8/biosynthesis , Jurkat Cells , Lymphocyte Activation/drug effects , Male , Myosin Light Chains/metabolism , Neutrophil Activation/drug effects , Protein Kinase Inhibitors/pharmacokinetics , Rats , Rats, Inbred Lew , Rats, Sprague-Dawley , Receptors, CCR2/biosynthesis
2.
J Med Chem ; 46(11): 2152-68, 2003 May 22.
Article in English | MEDLINE | ID: mdl-12747787

ABSTRACT

A novel series of substituted N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-N-(3-phenoxyphenyl)-trifluoro-3-amino-2-propanols is described which potently and reversibly inhibit cholesteryl ester transfer protein (CETP). Starting from the initial lead 1, various substituents were introduced into the 3-phenoxyaniline group to optimize the relative activity for inhibition of the CETP-mediated transfer of [3H]-cholesteryl ester from HDL donor particles to LDL acceptor particles either in buffer or in human serum. The better inhibitors in the buffer assay clustered among compounds in which the phenoxy group was substituted at the 3, 4, or 5 positions. In general, small lipophilic alkyl, haloalkyl, haloalkoxy, and halogen moieties increased potency relative to 1, while analogues containing electron-donating or hydrogen bond accepting groups exhibited lower potency. Compounds with polar or strong electron-withdrawing groups also displayed lower potency. Replacement of the phenoxy ring in 1 with either simple aliphatic or cycloalkyl ethers as well as basic heteroaryloxy groups led to reduced potency. From the better compounds, a representative series 4a-i was prepared as the chirally pure R(+) enantiomers, and from these, the 4-chloro-3-ethylphenoxy analogue was identified as a potent inhibitor of CETP activity in buffer (4a, IC50 0.77 nM, 59 nM in human serum). The simple R(+) enantiomer 4a represents the most potent acyclic CETP inhibitor reported. The chiral synthesis and biochemical characterization of 4a are reported along with its preliminary pharmacological assessment in animals.


Subject(s)
Aniline Compounds/chemical synthesis , Carrier Proteins/antagonists & inhibitors , Cholesterol Esters/metabolism , Glycoproteins , Hypolipidemic Agents/chemical synthesis , Propanolamines/chemical synthesis , Administration, Oral , Aniline Compounds/pharmacokinetics , Aniline Compounds/pharmacology , Animals , Cholesterol Ester Transfer Proteins , Cholesterol Esters/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Cricetinae , Humans , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/pharmacology , Lipoproteins , Mesocricetus , Mice , Mice, Inbred C57BL , Mice, Transgenic , Propanolamines/pharmacokinetics , Propanolamines/pharmacology , Stereoisomerism , Structure-Activity Relationship
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