The discovery of azetidine-piperazine di-amides as potent, selective and reversible monoacylglycerol lipase (MAGL) inhibitors.

Monoacylglycerol lipase (MAGL) is the enzyme that is primarily responsible for hydrolyzing the endocannabinoid 2-arachidononylglycerol (2-AG) to arachidonic acid (AA). It has emerged in recent years as a potential drug target for a number of diseases. Herein, we report the discovery of compound 6g from a series of azetidine-piperazine di-amide compounds as a potent, selective, and reversible inhibitor of MAGL.

The discovery of diazetidinyl diamides as potent and reversible inhibitors of monoacylglycerol lipase (MAGL).

Monoacylglycerol lipase (MAGL) has emerged as an attractive drug target because of its important role in regulating the endocannabinoid 2-arachidonoylglycerol (2-AG) and its hydrolysis product arachidonic acid (AA) in the brain. Herein, we report the discovery of a novel series of diazetidinyl diamide compounds 6 and 10 as potent reversible MAGL inhibitors. In addition to demonstrating potent MAGL inhibitory activity in the enzyme assay, the thiazole substituted diazetidinyl diamides 6d-l and compounds 10 were also effective at increasing 2-AG levels in a brain 2-AG accumulation assay in homogenized rat brain.

Global deletion of MGL in mice delays lipid absorption and alters energy homeostasis and diet-induced obesity.

Monoacylglycerol lipase (MGL) is a ubiquitously expressed enzyme that catalyzes the hydrolysis of monoacylglycerols (MGs) to yield FFAs and glycerol. MGL contributes to energy homeostasis through the mobilization of fat stores and also via the degradation of the endocannabinoid 2-arachidonoyl glycerol. To further examine the role of MG metabolism in energy homeostasis, MGL(-/-) mice were fed either a 10% (kilocalories) low-fat diet (LFD) or a 45% (kilocalories) high-fat diet (HFD) for 12 weeks.

Diabetogenic effect of a series of tricyclic delta opioid agonists structurally related to cyproheptadine.

The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic β-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog.

Ex vivo delta opioid receptor autoradiography: CNS receptor occupancy of two novel compounds over their antihyperalgesic dose range.

Discovered as part of an effort to identify delta opioid (DOPr or DOR) agonist analgesics, JNJ-20788560 and JNJ-39204880 exhibited high DOR affinity, with K(i) values of 1.7 and 2.0nM, respectively, and were selective for DOR over the mu opioid receptor (MOPr or MOR), with 596- and 122-fold selectivity, respectively.

Triazinediones as prokineticin 1 receptor antagonists. Part 1: SAR, synthesis and biological evaluation.

A series of guanidine triazinediones were identified as potent PK1 receptor antagonists. A compound in this series inhibited the PK1 invoked prosecretory response in rat ileum tissue.