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A 943931 dihydrochloride is a potent and selective H4 receptor antagonist. | [Biological Activity]
a 943931, is an h4r (one of histamine receptor subtypes) antagonist [1] with high affinities to h4rs of human (ki = 5 nm), rat (ki = 4 nm) and mouse (kb = 6 nm) [2].h4r is one of 4 known g-protein-coupled receptors (h1, h2, h3 and h4 receptors) of histamine for histamine to mediate its physiological functions [3].hmc-1 cells incubated with a 943931 at a concentration of 300 nm for 20 min inhibited the increase in aldh2 activity induced by h4r [4]. in microglia, a 943931 at a concentration of 10 μm partially abolish the release of tnf-α and il-6 induced by histamine at a concentration of 0.1 μg/ml [5]. in bone marrow-derived mast cells, a 943931 inhibited the shape change induced by histamine (ic50 = 0.38 μm) [6].intraperitoneal administration of a 943931 at a dose of 33 μmol/kg potently inhibited itch induced by h4r agonist in mice [6]. in several preclinical models, h4r had been shown to be linked to inflammation [7]. a 943931 had excellent antagonistic activity both in vivo and in vitro across multiple species, displayed good oral bioavailability (90%) and excellent metabolic stability. this compound displays good efficacy in rat pain models and is a good anti-inflammatory agent in mice [8]. a 943931 has an in vivo oral bioavailability of 34% and a half-life of 2.6 h in rats [2]. a 943931 efficaciously reduced acute inflammatory pains induced by formalin in the flinch model and by carrageenan in mechanical and thermal hyperalgesia models in rats [9]. | [References]
[1]. erich h. schneider and roland seifert. the histamine h4-receptor and the central and peripheral nervous system: a critical analysis of the literature. neuropharmacology, 2015, xxx:1-13.
[2]. rogier a. smits, herman d. lim, tiffany van der meer, et al. ligand based design of novel histamine h4 receptor antagonists; fragment optimization and analysis of binding kinetics. bioorg. med. chem. lett., 2012, 22: 461-467.
[3]. huaqing liu, robert j. altenbach, tracy l. carr, et al. cis-4-(piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (a-987306), a new histamine h4r antagonist that blocks pain responses against carrageenan-induced hyperalgesia. j. med. chem., 2008, 51:7094-7098.
[4]. silvia aldi, ken-ichi takano, kengo tomita, et al. histamine h4-receptors inhibit mast cell renin release in ischemia/reperfusion via pkcε-dependent aldehyde dehydrogenase type-2 activation. j. pharmacol. exp. ther., 2014, 349(3):508-17.
[5]. jin zhu, chen qu, xiang lu, et al. activation of microglia by histamine and substance p. cell physiol. biochem., 2014, 34(3):768-80.
[6]. harald engelhardt, rogier a smits, rob leurs, et al. a new generation of anti-histamines: histamine h4 receptor antagonists on their way to the clinic. curr. opin. drug discov. devel., 2009, 12(5):628-43.
[7]. jeffery m cowden, fuqu yu, homayon banie, et al. the histamine h4 receptor mediates inflammation and th17 responses in preclinical models of arthritis. ann. rheum. dis., 2014, 73:600-608.
[8]. rob leurs, paul l chazot, fiona c shenton, et al. molecular and biochemical pharmacology of the histamine h4 receptor. british journal of pharmacology, 2009, 157: 14-23.
[9]. david burns, niu shin, ravi jalluri, et al. annual reports in medicinal chemistry: h4 receptor antagonists and their potential therapeutic applications. burlington: academic press, 2014. |
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