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The present study evaluated the role of endogenous P-450 metabolites of arachidonic acid (AA) on autoregulation of renal blood flow in rats. Whole kidney and cortical blood flows were well autoregulated when renal perfusion pressure was varied from 150 to 100 mmHg. Infusion of 17-octadecynoic acid (17-ODYA) into the renal artery (33 nmol/min) increased cortical and papillary blood flows by 12.6 +/- 2.5 and 26.5 +/- 4.6%, respectively. After 17-ODYA, autoregulation of whole kidney and cortical blood flows was impaired. Intrarenal infusion of miconazole (8 nmol/min) had no effect on autoregulation of whole kidney, cortical, or papillary blood flows. 17-ODYA (1 microM) inhibited the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) and 11,12- and 14,15-epoxyeicosatrienoic acids (EETs) by renal preglomerular microvessels in vitro by 83.7 +/- 7.4% and 89.0 +/- 4.9%, respectively. Miconazole (1 microM) reduced the formation of EETs by 86.4 +/- 5.7%, but it had no effect on the production of 20-HETE. These results suggest that endogenous P-450 metabolites of AA, particularly 20-HETE, may participate in the autoregulation of renal blood flow.

Squalene epoxidase (SQLE), also known as squalene monooxygenase, catalyzes the stereospecific conversion of squalene to 2,3( S )-oxidosqualene, a key step in cholesterol biosynthesis. SQLE inhibition is targeted for the treatment of hypercholesteremia, cancer, and fungal infections. However, lack of structure-function understanding has hindered further progression of its inhibitors. We have determined the first three-dimensional high-resolution crystal structures of human SQLE catalytic domain with small molecule inhibitors (2.3 Å and 2.5 Å). Comparison with its unliganded state (3.0 Å) reveals conformational rearrangements upon inhibitor binding, thus allowing deeper interpretation of known structure-activity relationships. We use the human SQLE structure to further understand the specificity of terbinafine, an approved agent targeting fungal SQLE, and to provide the structural insights into terbinafine-resistant mutants encountered in the clinic. Collectively, these findings elucidate the structural basis for the specificity of the epoxidation reaction catalyzed by SQLE and enable further rational development of next-generation inhibitors.

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Monocyte chemoattractant protein-1 (MCP-1) is a major chemoattractant for monocytes and memory T cells by means of their binding to its specific cell-surface receptor, CC-chemokine receptor-2 (CCR2). CCR2 belongs to the G-protein-coupled seven-transmembrane receptor superfamily. The evidence in favor of CCR2 and MCP-1 having dominant roles in monocyte chemotaxis and chronic inflammation was provided by CCR2 and MCP-1 knockout mice. It has been recognized that CCR2 antagonists are potential therapeutic agents in preventing, treating, or ameliorating a CCR2-mediated inflammatory syndrome or disease such as psoriasis, uveitis, rheumatoid arthritis, multiple sclerosis, asthma, obesity, and chronic obstructive pulmonary disease. This review summarizes recent developments in small-molecule CCR2 antagonists disclosed by patent applications published between 2005 and 2008 and related publications.