306298-00-0Relevant articles and documents
Discovery and Optimization of Pyrazole Amides as Inhibitors of ELOVL1
Andreassi, John,Bonanno, Kenneth C.,Boucher, Christina,Bunnage, Mark E.,Chakilam, Ananthisrinivas,Charifson, Paul S.,Clark, Michael P.,Coll, Joyce,Come, Jon H.,Considine, Tony,Court, John J.,Crawford, Dan,Doyle, Elisabeth,Engtrakul, Juntyma,Furey, Brinley,Gagnon, Kevin J.,Gale-Day, Zachary,Gan, Lu,Gao, Hong,Gu, Wenxin,Huang, Yulin,Iyer, Ganesh,Jackson, Katrina L.,Kemper, Raymond,Kramer, Tal,Krueger, Elaine,Liang, Jianglin,Lu, Fan,Magavi, Sanjay S.,Maltais, Francois,Mohanty, Arun K.,Moody, Cameron S.,Morris, Mark,Nanthakumar, Suganthini,O'Dowd, Hardwin,Phillips, Jonathan,Sanders, Martin,Senter, Timothy J.,Song, Bin,Swett, Rebecca,Taylor, William,Vought, Bryan,Winquist, Ray,Zuccola, Harmon
, (2021/11/24)
Accumulation of very long chain fatty acids (VLCFAs) due to defects in ATP binding cassette protein D1 (ABCD1) is thought to underlie the pathologies observed in adrenoleukodystrophy (ALD). Pursuing a substrate reduction approach based on the inhibition of elongation of very long chain fatty acid 1 enzyme (ELOVL1), we explored a series of thiazole amides that evolved into compound 27─a highly potent, central nervous system (CNS)-penetrant compound with favorable in vivo pharmacokinetics. Compound 27 selectively inhibits ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts, lymphocytes, and microglia. In mouse models of ALD, compound 27 treatment reduced C26:0 VLCFA concentrations to near-wild-type levels in blood and up to 65% in the brain, a disease-relevant tissue. Preclinical safety findings in the skin, eye, and CNS precluded progression; the origin and relevance of these findings require further study. ELOVL1 inhibition is an effective approach for normalizing VLCFAs in models of ALD.
Preparation method of arylcyclopropane compound
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Paragraph 0089-0098, (2022/01/10)
The present invention discloses a method for preparing an arylcyclopropane compound, 1.0eq phenylacetonitrile and 1.1eq 1-bromo-2-chloroethane as the starting material, N, N- dimethylacetamide as a solvent, solvent dosage of 10V, plus 2.5eq sodium hydride
Chiral Bidentate Boryl Ligand Enabled Iridium-Catalyzed Enantioselective C(sp3)-H Borylation of Cyclopropanes
Shi, Yongjia,Gao, Qian,Xu, Senmiao
, p. 10599 - 10604 (2019/08/28)
We herein report an Ir-catalyzed enantioselective C(sp3)-H borylation of cyclopropanecarboxamides using a chiral bidentate boryl ligand for the first time. A variety of substrates with α-quaternary carbon centers could be compatible in this reaction to provide β-borylated products with good to excellent enantioselectivities. We have also demonstrated that the borylated products can be used as versatile precursors engaging in stereospecific transformations of C-B bonds, including the synthesis of a bioactive compound Levomilnacipran.
1,3-SUBSTITUED PYRAZOLE COMPOUNDS USEFUL FOR REDUCTION OF VERY LONG CHAIN FATTY ACIC LEVELS
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Paragraph 326; 334, (2018/06/30)
Disclosed are chemical entities which are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein Formula (I) has the structure: R1a, R1b, R2, R3, R4a, R4b and Y are as defined herein. These chemical entities are useful for reduction of very long chain fatty acid levels. These chemical entities and pharmaceutically acceptable compositions comprising such chemical entities can be useful for treating various diseases, disorders and conditions, such as adrenoleukodystrophy (ALD).
Piperazine derivatives useful as CCR5 antagonists
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Page column 92-93, (2010/02/05)
The use of CCR5 antagonists of the formula or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted phenyl, pyridyl, thiophenyl or naphthyl; R1is hydrogen or alkyl; R2is substituted phenyl, substituted heter
