124064-21-7Relevant academic research and scientific papers
Mechanistic pathways in CF3COOH-mediated deacetalization reactions
Li, Wei,Li, Jianchang,Wu, Yuchuan,Fuller, Nathan,Markus, Michelle A.
experimental part, p. 1077 - 1086 (2010/04/04)
(Chemical Equation Presented) It has been widely accepted that both the protection of carbonyls and the deprotection of acetals and ketals involve the participation of a water molecule: formation of acetals and ketals is a dehydration process, whereas the deprotection is often referred to as hydrolysis, which, as implied by its name, always requires the presence of water. Herein, we report experimental evidence and mechanistic investigations that provide an alternative view to this process. We have demonstrated that water is not required to convert acetals and ketals to the corresponding carbonyls. The 1H NMR experimental results revealed that the TFA-mediated transformation of acetal to aldehyde occurs via a hemiacetal TFA ester intermediate, which differentiates itself from the classic acid-catalyzed hydrolysis, where the hemiacetal is the putative intermediate responsible for the formation of the aldehyde. More interestingly, alcohols are not the final byproducts as they are in the classical hydrolysis, rather, the two alcohol molecules are converted to two TFA esters under the reaction conditions. On the basis of theNMRevidence, we have proposed that the two TFA esters are formed in two separate steps via a different mechanism along the reaction pathway. Formation of the TFA esters renders the reaction irreversible. To the best of our knowledge, the cascade reaction pathway presented by the TFA-mediated conversion of acetals and ketals to carbonyls has never been previously postulated.
Discovery of ecopladib, an indole inhibitor of cytosolic phospholipase A2α
Lee, Katherine L.,Foley, Megan A.,Chen, Lihren,Behnke, Mark L.,Lovering, Frank E.,Kirincich, Steven J.,Wang, Weiheng,Shim, Jaechul,Tam, Steve,Shen, Marina W. H.,Khor, SooPeang,Xu, Xin,Goodwin, Debra G.,Ramarao, Manjunath K.,Nickerson-Nutter, Cheryl,Donahue, Frances,Ku, M. Sherry,Clark, James D.,McKew, John C.
, p. 1380 - 1400 (2008/02/01)
The synthesis and structure-activity relationship of a series of indole inhibitors of cytosolic phospholipase A2α (cPLA 2α, type IVA phospholipase) are described. Inhibitors of cPLA2α are predicted to be efficacious in treating asthma as well as the signs and symptoms of osteoarthritis, rheumatoid arthritis, and pain. The introduction of a benzyl sulfonamide substituent at C2 was found to impart improved potency of these inhibitors, and the SAR of these sulfonamide analogues is disclosed. Compound 123 (Ecopladib) is a submicromolar inhibitor of cPLA2α in the GLU micelle and rat whole blood assays. Compound 123 displayed oral efficacy in the rat carrageenan air pouch and rat carrageenan-induced paw edema models.
Inhibition of cytosolic phospholipase A2α: Hit to lead optimization
McKew, John C.,Foley, Megan A.,Thakker, Paresh,Behnke, Mark L.,Lovering, Frank E.,Sum, Fuk-Wah,Tam, Steve,Wu, Kun,Shen, Marina W. H.,Zhang, Wen,Gonzalez, Mario,Liu, Shanghao,Mahadevan, Anu,Sard, Howard,Khor, Soo Peang,Clark, James D.
, p. 135 - 158 (2007/10/03)
Compound 1 was previously reported to be a potent inhibitor of cPLA 2α in both artificial monomeric substrate and cell-based assays. However, 1 was inactive in whole blood assays previously used to characterize cyclooxygenase and lipoxygenase inhibitors. The IC50 of 1 increased dramatically with cell number or lipid/detergent concentration. In an attempt to insert an electrophilic ketone between the indole and benzole acid moieties, we discovered that increasing the distance between the two moieties gave a compound with activity in the GLU (7-hydroxycoumarinyl-γ- linolenate) micelle assay, which contains lipid and detergent. Extensive structure-activity relationship work around this lead identified a potent pharmacophore for cPLA2α inhibition. The IC50s between the GLU micelle and rat whole blood assays correlated highly. No correlation was found for other parameters, including lipophilicity or acidity of the required acid functionality. Compounds 25, 39, and 94 emerged as potent, selective inhibitors of cPLA2α and represent well-validated starting points for further optimization.
Phenylcarboxylic acid derivatives
-
, (2008/06/13)
Phenylcarboxylic acid derivatives having the formula: STR1 wherein R1 and R2 are each H, halogen, alkyl, haloalkyl, alkanoyl, cycloalkyl, nitro, amino, --O--D--R5 (D is alkylene, R5 is H, amino, morpholino, carboxyl, phthalimido, phenyl, epoxy), substituted or unsubstituted phenoxy, substituted or unsubstituted phenylalkylamino, carboxylalkenyl, or both form alkylenedioxy; R3 is H, --E--R6 (E is alkylene, R6 is H, carboxyl, cyano, OH, phenylalkoxy, or halogen-substituted phenyl, or phenylcarbamoyl), --CO--G--R7 (G is alkylene, R7 is H, substituted or unsubstituted phenylcarbamoyl), substituted or unsubstituted benzoyl, alkenyl, carbamoyl, phenyl, or halophenyl; R4 is H or alkyl; A is alkylene, alkylene condensed with cycloalkyl ring, or alkenylene; B is alkylene or alkenylene; l is 0 or 1. Said compounds have fatty acid synthesis-inhibitory activity, cholesterol synthesis-inhibitory activity and are useful as antilipidemic agent, prophylactic and treating agent of artherosclerosis, prophylactic and treating agent of obesity, antidiabetics.
