Afferent nerves in the gut not only signal to the central nervous system but also provide a local efferent-like effect. This effect can modulate intestinal motility and secretion and is postulated to involve the transient receptor potential of the vanilloid type 1 (TRPV1). By using selective TRPV1 agonist and antagonists, we studied the efferent-like effect of afferent nerves in the isolated mouse jejunum. Mouse jejunal muscle strips were mounted in organ baths for isometric tension recordings. Jejunal strips contracted to the TRPV1 agonist capsaicin. Contractions to capsaicin showed rapid tachyphylaxis and were insensitive to tetrodotoxin, hexamethonium, atropine or L-nitroarginine. Capsaicin did not affect contractions to electrical stimulation of enteric motor nerves and carbachol. Tachykinin NK1, NK2 and NK3 receptor blockade by RP67580, nepadutant plus SR-142801 reduced contractions to capsaicin to a similar degree as contractions to substance P. The effect of the TRPV1 antagonists capsazepine, SB-366791, iodo-resiniferatoxin (iodo-RTX) and N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC) was studied. Capsazepine inhibited contractions not only to capsaicin but also those to carbachol. SB-366791 reduced contractions both to capsaicin and carbachol. Iodo-RTX partially inhibited the contractions to capsaicin without affecting contractions to carbachol. BCTC concentration-dependently inhibited and at the highest concentration used, abolished the contractions to capsaicin without affecting those to carbachol. From these results, we conclude that activation of TRPV1 in the mouse intestine induces a contraction that is mediated by tachykinins most likely released from afferent nerves. The TRPV1-mediated contraction does not involve activation of intrinsic enteric motor nerves. Of the TRPV1 antagonists tested, BCTC combined strong TRPV1 antagonism with TRPV1 selectivity.

The interaction between CC chemokine receptor 2 (CCR2) with monocyte chemoattractant proteins, such as MCP-1, regulates the activation and recruitment of inflammatory leukocytes. In this study, we characterized (S)-3-[3,4-difluoro-phenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxyl acid methyl ester (JNJ-27141491) as a noncompetitive and orally active functional antagonist of human (h)CCR2. JNJ-27141491 strongly suppressed hCCR2-mediated in vitro functions, such as MCP-1-induced guanosine 5Ј-O-(3-[35 S]thio)triphosphate binding; MCP-1, -3, and -4-induced Ca 2ϩ mobilization; and leukocyte chemotaxis toward MCP-1 (IC 50 ϭ 7-97 nM), whereas it had little or no effect on the function of other chemokine receptors tested. The inhibition of CCR2 function was both insurmountable and reversible, consistent with a noncompetitive mode of action. JNJ-27141491 blocked the binding of CCR2 is a G protein-coupled chemokine receptor, expressed on monocytes, macrophages, basophils, dendritic cells, natural killer cells, and activated T lymphocytes, that mediates the activation and movement of responsive leukocytes along a chemotactic gradient. CCR2 has two isoforms (CCR2A and CCR2B) that are generated by alternative splicing and differ only in their carboxyl-terminal tail. Leukocytes predominantly express the longer CCR2B variant (Tanaka et al., 2002). CCR2B (henceforth called CCR2) is activated by several members of the CC-chemokine subfamily, consisting of monocyte chemoattractant protein-1 (MCP-1/CCL2), MCP-2/CCL8, MCP-3/CCL7, MCP-4/CCL13, and MCP-5/CCL16. MCP-1 exclusively interacts with CCR2 and is therefore recognized as the prime CCR2 agonist. Engagement of CCR2 inhibits adenylyl cyclase, promotes intracellular calcium mobilization, stimulates mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways, and promotes che-

We recently reported the discovery of a series of 2-thioimidazoles as CCR2 antagonists. The most potent molecules of this series, the 4,5-diesters, were rapidly hydrolyzed to the inactive acids and were found to be metabolically unstable. Herein we describe the synthesis of a number of analogues with heterocyclic bioisosteric replacements of the ester group(s). Small 5-membered heterocyclic substituents at the 4-position gave highly potent CCR2 antagonists. Hydrolysis of the 5-ester is diminished, thus imparting these compounds with sufficient stability and systemic exposure after oral administration to warrant further study of the in vivo pharmacology of these functional CCR2 inhibitors.

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Imidazole derivatives R 01902-Mercaptoimidazoles, a New Class of Potent CCR2 Antagonists. -In a systematic study, the influence of the substitution pattern of the title compounds on the activity as CCR2 antagonists is examined. Compounds (VIII) are found to afford the best results. In particular, the (S)-isomers are potent and selective antagonists. -(VAN LOMMEN*, G.; DOYON, J.; COESEMANS, E.; BOECKX, S.; COOLS, M.; BUNTINX, M.; HERMANS, B.; VANWAUWE, J.; Bioorg. Med. Chem. Lett. 15 (2005) 3, 497-500; Inflamm. Res., Johnson & Johnson Pharm. Res. Dev., B-2340 Beerse, Belg.; Eng.) -M. Bohle 25-122