Sabnis_2022_ACS.Med.Chem.Lett_13_162

The endocannabinoid system consists of two G-protein coupled receptors, cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). CB1 is expressed in brain, peripherally in liver, gastrointestinal tract, pancreas, adipose tissue, and skeletal muscles. CB2 is predominantly expressed in immune cells such as monocytes and in skeletal and cardiac muscles. 2-Arachidonoylglycerol (2-AG) was identified as an additional endogenous ligand for the cannabinoid receptors. Monoacylglycerol lipase (MGL) is the serine hydrolase responsible for the degradation of 2-AG into arachidonic acid and glycerol in the central nervous system and peripheral tissue. Thus, MGL modulation offers an interesting strategy for potentiating the cannabinoid system. The primary advantage of this approach is that only brain regions where endocannabinoids are actively produced will be modulated. Therefore, by potentiating the cannabinoid system and attenuating proinflammatory cascades, MGL modulation, including MGL inhibition, offers a compelling therapeutic approach for the treatment of Alzheimers disease, Parkinsons disease, and Huntingtons disease. MGL is upregulated in aggressive human cancer cells and primary tumors. MGL modulators are potentially useful for the treatment of eyd conditions. The present application describes a series of novel aminocyclobutanes as monoacylglycerol lipase (MGL) modulators for the treatment of pain, psychiatric disorders, neurological disorders, cancers, and eye conditions. Further, the application discloses the compounds and their preparation, use, pharmaceutical composition, and treatment