Pandit J

References (4)

Title : Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation - McAllister_2018_J.Med.Chem_61_3008
Author(s) : McAllister LA , Butler CR , Mente S , O'Neil SV , Fonseca KR , Piro JR , Cianfrogna JA , Foley TL , Gilbert AM , Harris AR , Helal CJ , Johnson DS , Montgomery JI , Nason DM , Noell S , Pandit J , Rogers BN , Samad TA , Shaffer CL , da Silva RG , Uccello DP , Webb D , Brodney MA
Ref : Journal of Medicinal Chemistry , 61 :3008 , 2018
Abstract : Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.
ESTHER : McAllister_2018_J.Med.Chem_61_3008
PubMedSearch : McAllister_2018_J.Med.Chem_61_3008
PubMedID: 29498843
Gene_locus related to this paper: human-MGLL

Title : Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol Lipase - Butler_2017_J.Med.Chem_60_9860
Author(s) : Butler CR , Beck EM , Harris A , Huang Z , McAllister LA , Am Ende CW , Fennell K , Foley TL , Fonseca K , Hawrylik SJ , Johnson DS , Knafels JD , Mente S , Noell GS , Pandit J , Phillips TB , Piro JR , Rogers BN , Samad TA , Wang J , Wan S , Brodney MA
Ref : Journal of Medicinal Chemistry , 60 :9860 , 2017
Abstract : Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid (AA), a precursor to the proinflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient MAGL inhibitors, identified through a parallel medicinal chemistry approach that highlighted the improved efficiency of azetidine and piperidine-derived carbamates. The discovery and optimization of 3-substituted azetidine carbamate irreversible inhibitors of MAGL were aided by the generation of inhibitor-bound MAGL crystal structures. Compound 6, a highly efficient and selective MAGL inhibitor against recombinant enzyme and in a cellular context, was tested in vivo and shown to elevate central 2-AG levels at a 10 mg/kg dose.
ESTHER : Butler_2017_J.Med.Chem_60_9860
PubMedSearch : Butler_2017_J.Med.Chem_60_9860
PubMedID: 29148769
Gene_locus related to this paper: human-MGLL

Title : Discovery of a Selective Covalent Inhibitor of Lysophospholipase-like 1 (LYPLAL1) as a Tool to Evaluate the Role of this Serine Hydrolase in Metabolism - Ahn_2016_ACS.Chem.Biol_11_2529
Author(s) : Ahn K , Boehm M , Brown MF , Calloway J , Che Y , Chen J , Fennell KF , Geoghegan KF , Gilbert AM , Gutierrez JA , Kalgutkar AS , Lanba A , Limberakis C , Magee TV , O'Doherty I , Oliver R , Pabst B , Pandit J , Parris K , Pfefferkorn JA , Rolph TP , Patel R , Schuff B , Shanmugasundaram V , Starr JT , Varghese AH , Vera NB , Vernochet C , Yan J
Ref : ACS Chemical Biology , 11 :2529 , 2016
Abstract : Lysophospholipase-like 1 (LYPLAL1) is an uncharacterized metabolic serine hydrolase. Human genome-wide association studies link variants of the gene encoding this enzyme to fat distribution, waist-to-hip ratio, and nonalcoholic fatty liver disease. We describe the discovery of potent and selective covalent small-molecule inhibitors of LYPLAL1 and their use to investigate its role in hepatic metabolism. In hepatocytes, selective inhibition of LYPLAL1 increased glucose production supporting the inference that LYPLAL1 is a significant actor in hepatic metabolism. The results provide an example of how a selective chemical tool can contribute to evaluating a hypothetical target for therapeutic intervention, even in the absence of complete biochemical characterization.
ESTHER : Ahn_2016_ACS.Chem.Biol_11_2529
PubMedSearch : Ahn_2016_ACS.Chem.Biol_11_2529
PubMedID: 27391855
Gene_locus related to this paper: human-LYPLAL1

Title : Crystal structure of human squalene synthase. A key enzyme in cholesterol biosynthesis - Pandit_2000_J.Biol.Chem_275_30610
Author(s) : Pandit J , Danley DE , Schulte GK , Mazzalupo S , Pauly TA , Hayward CM , Hamanaka ES , Thompson JF , Harwood HJ
Ref : Journal of Biological Chemistry , 275 :30610 , 2000
Abstract : Squalene synthase catalyzes the biosynthesis of squalene, a key cholesterol precursor, through a reductive dimerization of two farnesyl diphosphate (FPP) molecules. The reaction is unique when compared with those of other FPP-utilizing enzymes and proceeds in two distinct steps, both of which involve the formation of carbocationic reaction intermediates. Because FPP is located at the final branch point in the isoprenoid biosynthesis pathway, its conversion to squalene through the action of squalene synthase represents the first committed step in the formation of cholesterol, making it an attractive target for therapeutic intervention. We have determined, for the first time, the crystal structures of recombinant human squalene synthase complexed with several different inhibitors. The structure shows that SQS is folded as a single domain, with a large channel in the middle of one face. The active sites of the two half-reactions catalyzed by the enzyme are located in the central channel, which is lined on both sides by conserved aspartate and arginine residues, which are known from mutagenesis experiments to be involved in FPP binding. One end of this channel is exposed to solvent, whereas the other end leads to a completely enclosed pocket surrounded by conserved hydrophobic residues. These observations, along with mutagenesis data identifying residues that affect substrate binding and activity, suggest that two molecules of FPP bind at one end of the channel, where the active center of the first half-reaction is located, and then the stable reaction intermediate moves into the deep pocket, where it is sequestered from solvent and the second half-reaction occurs. Five alpha helices surrounding the active center are structurally homologous to the active core in the three other isoprenoid biosynthetic enzymes whose crystal structures are known, even though there is no detectable sequence homology.
ESTHER : Pandit_2000_J.Biol.Chem_275_30610
PubMedSearch : Pandit_2000_J.Biol.Chem_275_30610
PubMedID: 10896663