- CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF
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Disclosed herein are small molecule calpain modulator compositions, pharmaceutical compositions, the use and preparation thereof.
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- SUBSTITUTED PYRAZOLE COMPOUNDS AS LPAR ANTAGONISTS
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of inflammatory diseases and disorders such as, for example, pulmonary fibrosis
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- Discovery of highly selective and orally active lysophosphatidic acid receptor-1 antagonists with potent activity on human lung fibroblasts
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Lysophosphatidic acid is a class of bioactive phospholipid that mediates most of its biological effects through LPA receptors, of which six isoforms have been identified. The recent results from LPA1 knockout mice suggested that blocking LPA1 signaling could provide a potential novel approach for the treatment of idiopathic pulmonary fibrosis. Here, we report the design and synthesis of pyrazole- and triazole-derived carbamates as LPA1-selective and LPA1/3 dual antagonists. In particular, compound 2, the most selective LPA1 antagonist reported, inhibited proliferation and contraction of normal human lung fibroblasts (NHLF) following LPA stimulation. Oral dosing of compound 2 to mice resulted in a dose-dependent reduction of plasma histamine levels in a murine LPA challenge model. Furthermore, we applied our novel antagonists as chemistry probes and investigated the contribution of LPA1/2/3 in mediating the pro-fibrotic responses. Our results suggest LPA1 as the major receptor subtype mediating LPA-induced proliferation and contraction of NHLF.
- Qian, Yimin,Hamilton, Matthew,Sidduri, Achyutharao,Gabriel, Stephen,Kondru, Rama,Narayanan, Arjun,Lucas, Matthew,Schoenfeld, Ryan C.,Laine, Dramane,Ren, Yonglin,Peng, Ruoqi,Chang, Kung-Ching,Fuentes, Maria E.,Stevenson, Christopher S.,Budd, David C.,Truitt, Terry,Hamid, Rachid,Chen, Yun,Zhang, Lin,Fretland, Adrian J.,Sanchez, Ruben Alvarez
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p. 7920 - 7939,20
(2020/08/24)
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- Action of Diazomethane on Methyl (Z(or E))-2-(Acylamino)cinnamates. A New Route to Methyl (Z)-2-(Acylamino)-3-methylcinnamates
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Diazomethane reacts with methyl (Z(or E))-2-acetamido(or benzamido)cinnamates (1,2) to afford regio- and stereospecifically (Z(or E))-4-phenyl-3-acetamido(or benzamido)-3-carbomethoxy-Δ1-pyrazolines (3,4). 3Z and 4Z undergo pyrolysis to afford
- Cativiela, Carlos,Villegas, Maria D. Diaz de,Mayoral, Jose A.,Melendez, Enrique
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p. 3167 - 3169
(2007/10/02)
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- Studies on Organic Fluorine Compounds. XLII. Synthesis and Reactions of Phenyltrifluoromethylacetylenes
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Phenyltrifluoromethylacetylene (4a) was synthesized by the pyrolysis of triphenylphosphonium α-(trifluoroacetyl)benzylide (3a), which was easily derived from benzyl halide (1a).This method can be used for the synthesis of 4-substituted-phenyltrifluoromethylacetylenes (4).The 1,3-dipolar reaction of 4 with diazomethane and phenyl azide proceeds readily to give trifluoromethylated pyrazoles and triazoles.Keywords - trifluoromethyl; acetylene; 1,3-dipolar reaction; intramolecular Wittig reaction; trifluoroacetylphosphonium ylide; pyrazole; diazomethane; phenyl azide
- Kobayashi, Yoshiro,Yamashita, Toshinori,Takahashi, Katsuhiro,Kuroda, Hisashi,Kumadaki, Itsumaro
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p. 4402 - 4409
(2007/10/02)
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