122213-92-7Relevant articles and documents
A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis
Hernndez-Torres, Gloria,Cipriano, Mariateresa,Hedn, Erika,Bj?rklund, Emmelie,Canales, Angeles,Zian, Debora,Feli, Ana,Mecha, Miriam,Guaza, Carmen,Fowler, Christopher J.,Ortega-Gutirrez, Silvia,Lpez-Rodrguez, Maria L.
supporting information, p. 13765 - 13770 (2015/01/16)
Monoacylglycerol lipase (MAGL) is the enzyme responsible for the inactivation of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibitors show analgesic and tissue-protecting effects in several disease models. However, the few efficient and selective MAGL inhibitors described to date block the enzyme irreversibly, and this can lead to pharmacological tolerance. Hence, additional classes of MAGL inhibitors are needed to validate this enzyme as a therapeutic target. Here we report a potent, selective, and reversible MAGL inhibitor (IC50 = 0.18 mm) which is active in vivo and ameliorates the clinical progression of a multiple sclerosis (MS) mouse model without inducing undesirable CB1-mediated side effects. These results support the interest in MAGL as a target for the treatment of MS.
Kinetic Studies of the Cyclization of the 6,6-Diphenyl-5-hexenyl Radical. A Test of the Accuracy of Rate Constants for Reactions of Hydrogen Transfer Agents
Ha, Chau,Horner, John H.,Newcomb, Martin,Varick, Thomas R.,Arnold, Bradley R.,Lusztyk, Janusz
, p. 1194 - 1198 (2007/10/02)
Cyclization of the 6,6-diphenyl-5-hexenyl radical (1) to the diphenylcyclopentylcarbinyl radical (2) was studied by indirect and direct methods.Indirect kinetic studies were accomplished by the PTOC-thiol method using hydrogen atom transfer trapping from
Pyridine compounds which are useful in treating a disease state characterized by an excess of platelet activating factors
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, (2008/06/13)
The invention relates to compounds of the formula STR1 wherein Y and Y' are hydrogen or taken together are O or S, *A is paraphenylene or *----(CH2)n --(X)s --(CH2)r ----, X is O, S or --CH=CH--, n or r, independently, are integers from 0 to 3, m is an integer from 0 to 1, s is an integer from 0 to 1, provided that when s is 1, n+m must be at least 2, t is an integer from 0 to 10, R1 and R2, independently, are lower alkyl, lower alkenyl or aryl, or one of R1 or R2 is hydrogen and the other is STR2 wherein W is STR3 --CH2 --CH2 --, --CH2 --, O, S, or STR4 and X1 is lower alkyl, phenyl unsubstituted or mono-, di- or trisubstituted by lower alkoxy, lower alkyl or halogen, and X2, X3 and X4, independently, are hydrogen, lower alkyl, lower alkoxy or halogen, R3 is hydrogen, lower alkyl or aryl, R4 is hydrogen, lower alkyl, aryl, aryl-lower alkyl or acyl, R5 is hydrogen or lower alkyl, R6 is hydrogen, lower alkyl, cycloalkyl, Het-lower alkyl or aryl, Het is a monocyclic 6-membered heteroaromatic radical containing one or two nitrogen atoms, which radical may be substituted by lower alkyl, halogen or aryl, and the asterisk denotes the point of attachment, and when R5 and R6 are different, their enantiomers and racemic mixtures thereof, when R1 and R2 are different, their geometric isomers, and pharmaceutically acceptable acid addition salts thereof.
Pentadienyl carboxamide derivatives as antagonists of platelet-activating factor
Guthrie,Kaplan,Mennona,Tilley,Kierstead,Mullin,LeMahieu,Zawoiski,O'Donnell,Crowley,Yaremko,Welton
, p. 1820 - 1835 (2007/10/02)
A series of N-[4-(3-pyridinyl)butyl]-5,5-disubstituted-pentadienamides was prepared and evaluated for PAF-antagonist activity. Compounds were assayed in vitro in a PAF-binding assay employing washed, whole dog platelets as the receptor source and in vivo after intravenous or oral administration for their ability to prevent PAF-induced bronchoconstriction in guinea pigs. Criteria required for good oral activity in the latter model include an (E,E)-5-phenyl-2,4-pentadienamide, a second phenyl or a four- or five-carbon alkyl moiety in the 5-position of the diene, and an (R)-[1-alkyl-4-(3-pyridinyl)butyl] substituent on the carboxamide nitrogen atom. The alkyl substituent on this side chain can be methyl, ethyl, or cyclopropyl. Two members of this series, [R-(E)]-5,5-bis(4-methoxyphenyl)-N-[1-methyl-4-(3-pyridinyl)butyl]-2,4- pentadienamide (31) and [R-(E,E)]-5-(4-methoxyphenyl)-N-[1-methyl-4-(3-pyridinyl)butyl]-2,4- decadienamide (58), were selected for further pharmacological evaluation. Both were found to be substantially longer acting after oral administration than the corresponding S enantiomers in the guinea pig bronchoconstriction assay. A second in vivo model used to evaluate PAF antagonists determines the ability of test compounds to decrease the area of skin wheals induced by an intradermal injection of PAF. In this model, using both rats and guinea pigs, compounds 31 and 58 were found to be as active as the reference PAF antagonist 3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-2-yl]-1-(4-morpholinyl)-1-propanone (45).
