ABSTRACT
A three substituted urea derivative, SA13353 (compound 1a), exhibited potent inhibitory activity against lipopolysaccharide (LPS)-induced TNF-alpha production. We focused on the 1,1-substituted moiety (R(1) and R(2)) of SA13353 and investigated substituent effects of this moiety on LPS-induced TNF-alpha production by oral administration in rats. The synthesis of the urea derivatives was performed rapidly in a one-pot manner using a manual synthesizer. Several compounds containing hydrophobic substituents at this moiety showed more potent inhibitory activities than SA13353.
Subject(s)
Tumor Necrosis Factor-alpha/biosynthesis , Urea/analogs & derivatives , Administration, Oral , Animals , Pyridines/pharmacology , Rats , Sulfenic Acids/chemistry , Urea/chemical synthesis , Urea/pharmacologyABSTRACT
We studied synthetic modifications of N-mercaptoacylamino acid derivatives to develop a new class of leukotriene A(4) (LTA(4)) hydrolase inhibitors. S-(4-Dimethylamino)benzyl-l-cysteine derivative 2a (SA6541) showed inhibitory activity against LTA(4) hydrolase (IC(50), 270nM) and selectivity over other metallopeptidases except angiotensin-converting enzyme (ACE, IC(50), 520nM). Modification at the para-substituent of the phenyl ring of compound 2a improved LTA(4) hydrolase inhibitory activity as well as selectivity over ACE. Finally, we obtained S-(4-cyclohexyl)benzy-l-cysteine derivatives 11l and 16i as potent and selective LTA(4) hydrolase inhibitors.
Subject(s)
Cysteine/chemistry , Epoxide Hydrolases/antagonists & inhibitors , Sulfhydryl Compounds/chemical synthesis , Sulfhydryl Compounds/pharmacology , Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Angiotensin-Converting Enzyme Inhibitors/chemistry , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Drug Evaluation, Preclinical , Models, Molecular , Quantitative Structure-Activity Relationship , Sulfhydryl Compounds/chemistryABSTRACT
We studied the synthetic modification of structurally similar N-mercaptoacyl-L-proline and (4R)-N-mercaptoacylthiazolidine-4-carboxylic acid to obtain potent leukotriene A(4) (LTA(4)) hydrolase inhibitors. An N-mercaptoacyl group, (2S)-3-mercapto-2-methylpropionyl group, was effective for both scaffolds. Additional introduction of a large substituent such as 4-isopropylbenzylthio (3f), 4-tert-butylbenzylthio (3l) or 4-cyclohexylbenzylthio group (3m) with (S)-configuration at the C(4) position of proline yielded much more potent LTA(4) hydrolase inhibitors (IC(50); 52, 31, and 34 nM, respectively) than captopril (IC(50); 630,000 nM).
Subject(s)
Carboxylic Acids/chemical synthesis , Epoxide Hydrolases/antagonists & inhibitors , Proline/analogs & derivatives , Proline/chemical synthesis , Sulfhydryl Compounds/pharmacology , Thiazolidines/pharmacology , Animals , Carboxylic Acids/chemistry , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Humans , Inhibitory Concentration 50 , Leukotriene A4/metabolism , Models, Chemical , Proline/chemistry , Proline/pharmacology , Structure-Activity RelationshipABSTRACT
Tumor necrosis factor-alpha (TNF-alpha) is known to play a crucial role in the pathogenesis of rheumatoid arthritis. In the present study, we demonstrate the effects of SA13353 (1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea), a novel orally active inhibitor of TNF-alpha production, in animal models, and its mechanism of action on TNF-alpha production. SA13353 significantly inhibited lipopolysaccharide (LPS)-induced TNF-alpha production in a dose-dependent manner in rats. Moreover, SA13353 exhibited a binding affinity for the rat vanilloid receptor and increased neuropeptide release from the rat dorsal root ganglion neurons. However, its effects were blocked by pretreatment with the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine. The ability of SA13353 and capsaicin to inhibit LPS-induced TNF-alpha production was eliminated by sensory denervation or capsazepine pretreatment in vivo. Although they inhibited LPS-induced TNF-alpha production in mice, these effects were not observed in TRPV1 knockout mice. SA13353 provoked the release of neuropeptides without nerve inactivation, even when chronically administered to rats. These results suggest that SA13353 inhibits TNF-alpha production through activation of capsaicin-sensitive afferent neurons mediated via TRPV1 in vivo. Post-onset treatment of SA13353 strongly reduced the hindpaw swelling and joint destruction associated with collagen-induced arthritis in rats. Thus, SA13353 is expected to be a novel anti-arthritic agent with a unique mechanism of action.
Subject(s)
Capsaicin/pharmacology , Neurons, Afferent/drug effects , Pyridines/pharmacology , TRPV Cation Channels/physiology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Urea/analogs & derivatives , Animals , Arthritis, Experimental/prevention & control , Calcitonin Gene-Related Peptide/metabolism , Capsaicin/analogs & derivatives , Dose-Response Relationship, Drug , Female , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurons, Afferent/physiology , Rats , Rats, Inbred Lew , Somatostatin/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , Urea/pharmacologyABSTRACT
A series of ethacrynic acid (ECA) derivatives were synthesized and examined for ocular hypotensive activity. Efficacy was evaluated in a cell-shape assay, using human trabecular meshwork cells, and cytotoxicity in a (3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay, using cultured bovine trabecular meshwork cells. Many of the derivatives demonstrated efficacy equal to or greater than that of ECA. SA9000 was selected as the most promising candidate for a novel ocular hypotensive drug with few side effects.
Subject(s)
Cytoskeleton/drug effects , Ethacrynic Acid/analogs & derivatives , Ethacrynic Acid/pharmacology , Trabecular Meshwork/drug effects , Animals , Cattle , Cells, Cultured , Cytoskeleton/physiology , Ethacrynic Acid/chemistry , Trabecular Meshwork/physiologyABSTRACT
We investigated the effects of marimastat, an inhibitor of TNF-alpha converting enzyme and matrix metalloproteinases, and anti-TNF-alpha antibodies on a murine model for sepsis, and on arthritis in human TNF-alpha transgenic mice. Marimastat (25-200 mg/kg) inhibited lipopolysaccharide (LPS)-induced soluble TNF-alpha production in mice in a dose-dependent manner. At an oral dose of 200 mg/kg, marimastat almost completely inhibited LPS-induced soluble TNF-alpha production, but only slightly delayed LPS lethality. On the other hand, anti-TNF-alpha antibodies completely abolished LPS-induced morbidity. In addition, anti-TNF-alpha antibodies, but not marimastat (200 mg/kg/day), inhibited the development of arthritis in human TNF-alpha transgenic mice. These results suggest that cell surface TNF-alpha may be important in the pathogenesis of murine models for sepsis and arthritis.