Glia-activating factor (GAF) is a novel heparin-binding growth factor purified from the culture supernatant of a human glioma cell line. It shows a spectrum of activity slightly different from those of other known growth factors. We have isolated the cDNA which encodes human GAF. A homology search revealed that GAF would be the ninth member of the FGF family, and we therefore call it FGF-9. The human FGF-9 cDNA cloned by using oligonucleotide probes encoded a polypeptide consisting of 208 amino acids. Sequence similarity to other members of the FGF family was estimated to be around 30%o. Two cysteine residues and other consensus sequences in family members were also well conserved in the FGF-9 sequence. FGF-9 was found to have no typical signal sequence in its N terminus like those in acidic FGF and basic FGF. Acidic FGF and basic FGF are known not to be secreted from cells in a conventional manner. However, FGF-9 was found to be secreted from cells after synthesis despite its lack of a typical signal sequence. It could be detected exclusively in the culture medium of cDNA-transfected COS cells. The amino acid sequence of proteins purified from culture supernatant of the CHO cell line, which was cDNA transfected and selected as a high producer of FGF-9, showed that no peptides were cleaved from the N terminus except the initiation methionine. The rat FGF-9 cDNA was also cloned, and the structural analysis indicated that the FGF-9 gene is highly conserved.Expression of the FGF-9 gene could be detected in the brain and kidney of the adult rat. Restricted gene expression in organs and the unique secretion nature of the protein suggest that FGF-9 plays a physiological role which differs from those of well-characterized acidic FGF and basic FGF.
The p38 mitogen-activated protein (MAP) kinase has been implicated in the proinflammatory cytokine signal pathway, and its inhibitors are potentially useful for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease. To develop a new drug for RA, we synthesized a novel series of 4-phenyl-5-pyridyl-1,3-thiazoles and evaluated their inhibition of p38 MAP kinase, lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor-alpha (TNF-alpha) from human monocytic THP-1 cells in vitro, and LPS-induced TNF-alpha production in vivo in mice. During the course of the study, we found that these compounds risk the inhibition of cytochrome P450 (CYP) isoforms by coordination of the 4-pyridyl nitrogen with heme iron. We therefore investigated the effects of substitution at the 2-position of the pyridyl ring on the inhibitory activity of p38 MAP kinase and CYPs in more detail. As a result, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (8h, TAK-715) exhibited potent inhibitory activity in these assays (inhibition of p38alpha, IC50 = 7.1 nM; LPS-stimulated release of TNF-alpha from THP-1, IC50 = 48 nM; LPS-induced TNF-alpha production in mice, 87.6% inhibition at 10 mg/kg, po) and no inhibitory activity for major CYPs, including CYP3A4. This compound also showed good bioavailability in mice and rats and significant efficacy in a rat adjuvant-induced arthritis model. Compound 8h was selected as a clinical candidate and is now under clinical investigation for the treatment of RA.
Glia-activating factor (GAF) is a novel heparin-binding growth factor purified from the culture supernatant of a human glioma cell line. It shows a spectrum of activity slightly different from those of other known growth factors. We have isolated the cDNA which encodes human GAF. A homology search revealed that GAF would be the ninth member of the FGF family, and we therefore call it FGF-9. The human FGF-9 cDNA cloned by using oligonucleotide probes encoded a polypeptide consisting of 208 amino acids. Sequence similarity to other members of the FGF family was estimated to be around 30%. Two cysteine residues and other consensus sequences in family members were also well conserved in the FGF-9 sequence. FGF-9 was found to have no typical signal sequence in its N terminus like those in acidic FGF and basic FGF. Acidic FGF and basic FGF are known not to be secreted from cells in a conventional manner. However, FGF-9 was found to be secreted from cells after synthesis despite its lack of a typical signal sequence. It could be detected exclusively in the culture medium of cDNA-transfected COS cells. The amino acid sequence of proteins purified from culture supernatant of the CHO cell line, which was cDNA transfected and selected as a high producer of FGF-9, showed that no peptides were cleaved from the N terminus except the initiation methionine. The rat FGF-9 cDNA was also cloned, and the structural analysis indicated that the PGF-9 gene is highly conserved. Expression of the FGF-9 gene could be detected in the brain and kidney of the adult rat. Restricted gene expression in organs and the unique secretion nature of the protein suggest that FGF-9 plays a physiological role which differs from those of well-characterized acidic FGF and basic FGF.
Tumor necrosis factor-a (TNF-a) is a pro-inflammatory cytokine, mainly produced by activated monocytes and macrophages. Excessive production of TNF-a is believed to underlie the progression of many serious inflammatory diseases, such as rheumatoid arthritis (RA), Crohn's disease and psoriasis. 1,2) Recent clinical data, obtained using chimeric TNF-a antibodies 3,4) and soluble TNF-a receptor fusion proteins 5) in the treatment of RA, have confirmed the important role of TNF-a in these inflammatory conditions. These agents are generally well tolerated but have drawbacks relating to patient cost, efficiency of production, and administration by injection. Therefore, inflammation research has focused on the development of orally active small molecular inhibitors of cytokine release.A serine/threonine kinase termed p38 mitogen-activated protein (MAP) kinase is a member of the stress-activated protein kinases and is considered as an attractive target. The prototypical p38 MAP kinase inhibitor SB 203580 (Fig. 1) showed inhibitory activity in vivo against pro-inflammatory cytokine production in both mice and rats, 6) and several novel structural classes of p38 MAP kinase inhibitors have been demonstrated to efficiently reduce cytokine levels. 7) Thus, the regulation of TNF-a via the inhibition of p38 MAP kinase is expected to have beneficial effects in the treatment of inflammatory diseases. Although the efforts to develop small molecule agents for p38 MAP kinase have not yet yielded an agent ready to market, several inhibitors are presently under investigation in human clinical trials.We have previously reported that 4-phenyl-5-pyridyl-1,3-thiazole derivatives showed strong anti-inflammatory activities 8,9) but the anti-inflammatory mechanism of these compounds was not well-known. In a continuing effort to elucidate the mechanism, we found that 2-amino-4-phenyl-5-pyridyl-1,3-thiazole derivatives had potent adenosine receptor antagonistic activity and phosphodiesterase inhibitory activity.10) These receptors and enzymes are related to adenosine or adenosine-3,5-triphosphate (ATP), suggesting that 4-phenyl-5-pyridyl-1,3-thiazole derivatives mimic adenosine and its related substrates. Taking these results into consideration, we explored the 4-phenyl-5-pyridyl-1,3-thiazole template, including rarely reported 2-acetylaminothiazole compounds. Herein, we report the synthesis and biological activities of a novel series of 4-phenyl-5-pyridyl-1,3-thiazole derivatives as p38 MAP kinase inhibitors. ChemistryThe general approach for the synthesis of 4,5-disubstituted 2-acetylamino-1,3-thiazoles 7 is outlined in Chart 1. The 1-benzoyl-2-methylaziridines 2 were prepared from the corresponding acid chloride and commercially available 2-methylaziridine according to the Schotten-Baumann procedure. The lithium anion of methylpyridine 3 was condensed with 1-benzoyl-2-methylaziridines 2 and the resulting ketones 4 Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd.; 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka, 532-8686, Ja...
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