126410-30-8Relevant articles and documents
Structure Kinetics Relationships and Molecular Dynamics Show Crucial Role for Heterocycle Leaving Group in Irreversible Diacylglycerol Lipase Inhibitors
Janssen, Antonius P.A.,Van Hengst, Jacob M.A.,Béquignon, Olivier J.M.,Deng, Hui,Van Westen, Gerard J.P.,Van Der Stelt, Mario
supporting information, p. 7910 - 7922 (2019/10/11)
Drug discovery programs of covalent irreversible, mechanism-based enzyme inhibitors often focus on optimization of potency as determined by IC50-values in biochemical assays. These assays do not allow the characterization of the binding activity (Ki) and reactivity (kinact) as individual kinetic parameters of the covalent inhibitors. Here, we report the development of a kinetic substrate assay to study the influence of the acidity (pKa) of heterocyclic leaving group of triazole urea derivatives as diacylglycerol lipase (DAGL)-α inhibitors. Surprisingly, we found that the reactivity of the inhibitors did not correlate with the pKa of the leaving group, whereas the position of the nitrogen atoms in the heterocyclic core determined to a large extent the binding activity of the inhibitor. This finding was confirmed and clarified by molecular dynamics simulations on the covalently bound Michaelis-Menten complex. A deeper understanding of the binding properties of covalent serine hydrolase inhibitors is expected to aid in the discovery and development of more selective covalent inhibitors.
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
, 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.
A synthetic zara Wei intermediates (by machine translation)
-
Paragraph 0014; 0024-0025, (2017/07/22)
The invention discloses a method for synthesizing zara Wei intermediate (1S, 2R) - 1 - epoxy ethyl - 2 - phenylethyl amino acid tert-butyl, comprises the following steps: step 1, the 1 - phenyl - 3 - butene - 2 - one in the chiral amino alcohol catalyst 1 under the action of the 2 - nitro-benzylamine generating asymmetric reduction ammoniation reaction, to obtain (S)- 3 - amino - 4 - phenyl - 1 - butene; step 2, will (S)- 3 - amino - 4 - phenyl - 1 - butene with di-T-n-butyl reaction for protecting amino group to obtain (S)- 3 - N - tert-butoxycarbonyl amino - 4 - phenyl - 1 - butene; step 3, will be (S)- 3 - N - tert-butoxycarbonyl amino - 4 - phenyl - 1 - butene in the hand natural spiral alkene phenolalkone iron complex catalyst 2 under the action of the air oxygen in the epoxidation reaction, to obtain (1S, 2R) - 1 - epoxy ethyl - 2 - phenylethyl amino acid tert-butyl. The present invention provides of the important intermediate zara Wei (1S, 2R) - 1 - epoxy ethyl - 2 - phenylethyl amino acid tert-butyl synthetic method of the raw material is cheap, mild reaction conditions, the operation is simple, the synthesis efficiency is high, it is suitable for industrial production, in order to prepare zara Wei and intermediate provides a new way. (by machine translation)
