756462-76-7Relevant articles and documents
Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding
Deng, Hui,Kooijman, Sander,Van Den Nieuwendijk, Adrianus M. C. H.,Ogasawara, Daisuke,Van der Wel, Tom,Van Dalen, Floris,Baggelaar, Marc P.,Janssen, Freek J.,Van Den Berg, Richard J. B. H. N.,Den Dulk, Hans,Cravatt, Benjamin F.,Overkleeft, Herman S.,Rensen, Patrick C. N.,Van der Stelt, Mario
supporting information, p. 428 - 440 (2017/04/26)
Triazole ureas constitute a versatile class of irreversible inhibitors that target serine hydrolases in both cells and animal models. We have previously reported that triazole ureas can act as selective and CNS-active inhibitors for diacylglycerol lipases (DAGLs), enzymes responsible for the biosynthesis of 2-arachidonoylglycerol (2-AG) that activates cannabinoid CB1 receptor. Here, we report the enantio- and diastereoselective synthesis and structure-activity relationship studies. We found that 2,4-substituted triazole ureas with a biphenylmethanol group provided the most optimal scaffold. Introduction of a chiral ether substituent on the 5-position of the piperidine ring provided ultrapotent inhibitor 38 (DH376) with picomolar activity. Compound 38 temporarily reduces fasting-induced refeeding of mice, thereby emulating the effect of cannabinoid CB1-receptor inverse agonists. This was mirrored by 39 (DO34) but also by the negative control compound 40 (DO53) (which does not inhibit DAGL), which indicates the triazole ureas may affect the energy balance in mice through multiple molecular targets.
An access to (Z)-ethylenic pseudodipeptides based on ring-closing metathesis
Boucard, Valérie,Sauriat-Dorizon, Hélène,Guibé, Fran?ois
, p. 7275 - 7290 (2007/10/03)
A new access to enantiopure (Z)-ethylenic pseudopeptides, starting from the chiral pool of amino acids and enantiopure 2-substituted-but-3-enoic acids is proposed and illustrated by the syntheses of the (Z)-ethylenic pseudopeptidic analogs of L-Phe-L-Phe, L-Phe-D-Phe, L-Phe-L-Val, L-Phe-D-Val and racemic (LL,DD) and (LD,DL) (phenyl)Gly-Phe. The key-steps of these syntheses are a ring-closing metathesis, catalysed by Grubbs' ruthenium alkykidene complexes, on diethylenic amides and the hydrolytic cleavage of the resulting dihydropyridones under mild conditions through intermediate formation of cyclic imidates.
