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Doshi PD Giri JG Abegg AL Favara JP Huynh MS Kahn LE Minnerly JC Pegg LE Villani-Price D Siegel NR Staten NR Thomas JW McKearn JP Smith WG 《Experimental hematology》2001,29(10):1177-1184
OBJECTIVE: The signaling pathways induced by promegapoietin (PMP), a family of chimeric growth factors that activate the human IL-3 and c-Mpl receptors, were investigated. METHODS: The biological activity of PMP was examined by receptor binding, cell proliferation, ex vivo expansion of hematopoietic progenitor cells, and in vivo production of platelets. The activation of signaling pathways was examined by Western blot and Northern blot analyses. RESULTS: Two PMP molecules, PMP-1 and PMP-1a, induced proliferation of cells expressing the IL-3 receptor, c-Mpl, or both receptors and bound to the IL-3 receptor and c-Mpl with high affinity. Ex vivo expansion assays using human bone marrow CD34(+) cells suggested that PMP-1 induced greater total cellular expansion as well as expansion of CD41(+) megakaryocytic precursor cells than IL-3 or c-Mpl ligand alone. Subcutaneous administration of 50 microg/kg of PMP-1 for 10 days to rhesus monkeys resulted in increased platelet production in vivo from a baseline of 357 +/- 45 x 10(3) cells/mL to 1376 +/- 151 x 10(3) cell/mL. PMP-1 induced phosphorylation of the beta(c) subunit of IL-3 receptor and c-Mpl, JAK2, and STAT5b, but not STAT3. PMP-1 induced greater expression of Pim-1, c-Myc, and cyclin D2 than did either an IL-3 receptor agonist or c-Mpl receptor agonist alone. The magnitude of induction of early response genes was similar for PMP and the coaddition of IL-3 receptor agonist and c-Mpl receptor agonist. CONCLUSION: PMP combines the biological activities of IL-3 and c-Mpl ligand in a single molecule that can simultaneously activate signaling pathways induced by both these ligands. 相似文献
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Penning TD Russell MA Chen BB Chen HY Liang CD Mahoney MW Malecha JW Miyashiro JM Yu SS Askonas LJ Gierse JK Harding EI Highkin MK Kachur JF Kim SH Villani-Price D Pyla EY Ghoreishi-Haack NS Smith WG 《Journal of medicinal chemistry》2002,45(16):3482-3490
Leukotriene B(4) (LTB(4)) is a potent, proinflammatory mediator involved in the pathogenesis of a number of diseases including inflammatory bowel disease, psoriasis, rheumatoid arthritis, and asthma. The enzyme LTA(4) hydrolase represents an attractive target for pharmacological intervention in these disease states, since the action of this enzyme is the rate-limiting step in the production of LTB(4). Our previous efforts focused on the exploration of a series of analogues related to screening hit SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) and resulted in the identification of potent, orally active inhibitors such as 2. Additional structure-activity relationship studies around this structural class resulted in the identification of a series of alpha-, beta-, and gamma-amino acid analogues that are potent inhibitors of the LTA(4) hydrolase enzyme and demonstrated good oral activity in a mouse ex vivo whole blood LTB(4) production assay. The efforts leading to the identification of clinical candidate SC-57461A (8d, 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid) are described. 相似文献
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Leslie J Askonas James F Kachur Doreen Villani-Price Chi-Dean D Liang Mark A Russell Walter G Smith 《The Journal of pharmacology and experimental therapeutics》2002,300(2):577-582
Leukotriene (LT) B(4) is an inflammatory mediator that has been implicated in the pathogenesis of various diseases, including inflammatory bowel disease and psoriasis. As the rate-limiting step for LTB(4) production, LTA(4) hydrolase represents an attractive target for therapeutic agents that interfere with LTB(4) production. In the present study we evaluated a chemically novel compound designated SC-57461A (3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl) as an inhibitor of LTA(4) hydrolase. Pharmacological comparisons are made to its free acid SC-57461. SC-57461A is a potent competitive inhibitor of recombinant human LTA(4) hydrolase when either LTA(4) (IC(50) = 2.5 nM, K(i) = 23 nM) or peptide substrates (IC(50) = 27 nM) are used. In human whole blood, the IC(50) for calcium ionophore-induced LTB(4) production was 49 nM, indicative of good cell penetration. Whole blood production of the cyclooxygenase metabolite thromboxane B(2) was not affected. SC-57461A was also active in several other species, including mouse, rat, dog, and rhesus monkey. The data indicate that SC-57461A is a potent and selective inhibitor of LTA(4) hydrolase. 相似文献
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Penning TD Chandrakumar NS Chen BB Chen HY Desai BN Djuric SW Docter SH Gasiecki AF Haack RA Miyashiro JM Russell MA Yu SS Corley DG Durley RC Kilpatrick BF Parnas BL Askonas LJ Gierse JK Harding EI Highkin MK Kachur JF Kim SH Krivi GG Villani-Price D Pyla EY Smith WG 《Journal of medicinal chemistry》2000,43(4):721-735
Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay. 相似文献
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James F Kachur Leslie J Askonas Doreen Villani-Price Nayereh Ghoreishi-Haack Suzanne Won-Kim Chi-Dean D Liang Mark A Russell Walter G Smith 《The Journal of pharmacology and experimental therapeutics》2002,300(2):583-587
Leukotriene (LT) A(4) hydrolase is a dual function enzyme that is essential for the conversion of LTA(4) to LTB(4) and also possesses an aminopeptidase activity. SC-57461A (3-[methyl[3-[4-phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl) is a potent inhibitor of human recombinant LTA(4) hydrolase (epoxide hydrolase and aminopeptidase activities, K(i) values = 23 and 27 nM, respectively) as well as calcium ionophore-induced LTB(4) production in human whole blood (IC(50) = 49 nM). In the present study, we investigated its action in several animal models. Oral activity was evident from the ability of the compound to inhibit mouse ex vivo calcium ionophore-stimulated blood LTB(4) production with ED(50) values at 1.0 and 3.0 h of 0.2 and 0.8 mg/kg, respectively. A single oral dose of 10 mg/kg SC-57461A blocked mouse ex vivo LTB(4) production 67% at 18 h and 44% at 24 h, suggesting a long pharmacodynamic half-life. In a rat model of ionophore-induced peritoneal eicosanoid production, SC-57461 inhibited LTB(4) production in a dose-dependent manner (ED(50) = 0.3-1 mg/kg) without affecting LTC(4) or 6-keto-prostaglandin F(1alpha) production. Oral pretreatment with SC-57461 in a rat reversed passive dermal Arthus model blocked LTB(4) production with an ED(90) value of 3 to 10 mg/kg, demonstrating good penetration of drug into skin. Plasma level of intact SC-57461 (3 h after oral gavage dosing with 3 mg/kg) was 0.4 microg/ml, which corresponds to >80% inhibition of dermal LTB(4) production. Oral or topical pretreatment with SC-57461A 1 h before challenge with arachidonic acid blocked ear edema in the mouse. SC-57461A is a competitive, selective, and orally active inhibitor of LTA(4) hydrolase in vivo, making it useful to explore the contribution of LTB(4) to a number of inflammatory diseases. 相似文献
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D Villani-Price D C Yang R E Walsh D J Fretland R H Keith G Kocan J F Kachur T S Gaginella B S Tsai 《The Journal of pharmacology and experimental therapeutics》1992,260(1):187-191
7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8- propyl-2H-1-benzopyran-2-carboxylic acid (SC-41930), a leukotriene B4 (LTB4) receptor antagonist with anti-inflammatory activity in animal models of colitis, was evaluated for effects on superoxide, LTB4 and prostaglandin E2 production. SC-41930 inhibited human neutrophil (PMN) superoxide generation maximally stimulated by f-Met-Leu-Phe (IC50 4 microM) and C5a (IC50 approximately 12 microM). Moreover, postreceptor stimulation of superoxide production by NaF (a G protein activator), but not by phorbol myristate acetate, was significantly inhibited by SC-41930, indicating that SC-41930 may act via attenuation of a G protein-mediated signal transduction. SC-41930 also inhibited A23187-stimulated LTB4 production (IC50 5.3 microM) in human PMN as well as LTB4 (IC50 2.1 microM) and prostaglandin E2 (IC50 2.9 microM) production in HL-60 cells. When coinjected intradermally (400 micrograms/site), SC-41930 inhibited A23187-stimulated increases in LTB4 levels in guinea pig skin. SC-41930 inhibited human synovial phospholipase A2 (IC50 72 microM), A23187-stimulated 5-hydroxy-eicosatetranoic acid production in human PMN (IC50 8.5 microM), and rat peritoneal leukotriene A4 hydrolase (IC50 20 microM), but not ram seminal vesical cyclooxygenase. The results suggest that the anti-inflammatory activity of SC-41930 could be attributed to postreceptor inhibition of inflammatory mediator production by PMN and other cells in addition to antagonism of PMN LTB4 receptors. 相似文献
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Penning T. D. Djuric S. W. Docter S. H. Yu S. S. Spangler D. Anglin C. P. Fretland D. J. Kachur J. F. Keith R. H. Tsai B. S. Villani-Price D. Widomski D. L. 《Inflammation research》1993,39(1):C11-C13
SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, is a selective, orally active, LTB4 receptor antagonist currently in clinical trials for psoriasis and ulcerative colitis. Exhaustive SAR studies found a potential backup compound, SC-50605, which was 7–16 times more potent than SC-41930 in LTB4 receptor binding, chemotaxis and degranulation assays. SC-50605 also inhibited LTB4-induced intradermal chemotaxis in cavine skin at an oral dose of 0.10 mg/kg and displayed good activity in animal models of colitis and epidermal inflammation both orally and topically. 相似文献
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