Novel tricyclic small molecule inhibitors of Nicotinamide N-methyltransferase for the treatment of metabolic disorders.

Nicotinamide N-methyltransferase (NNMT) is a metabolic regulator that catalyzes the methylation of nicotinamide (Nam) using the co-factor S-adenosyl-L-methionine to form 1-methyl-nicotinamide (MNA). Overexpression of NNMT and the presence of the active metabolite MNA is associated with a number of diseases including metabolic disorders. We conducted a high-throughput screening campaign that led to the identification of a tricyclic core as a potential NNMT small molecule inhibitor series. Elaborate medicinal chemistry efforts were undertaken and hundreds of analogs were synthesized to understand the structure activity relationship and structure property relationship of this tricyclic series. A lead molecule, JBSNF-000028, was identified that inhibits human and mouse NNMT activity, reduces MNA levels in mouse plasma, liver and adipose tissue, and drives insulin sensitization, glucose modulation and body weight reduction in a diet-induced obese mouse model of diabetes. The co-crystal structure showed that JBSNF-000028 binds below a hairpin structural motif at the nicotinamide pocket and stacks between Tyr-204 (from Hairpin) and Leu-164 (from central domain). JBSNF-000028 was inactive against a broad panel of targets related to metabolism and safety. Interestingly, the improvement in glucose tolerance upon treatment with JBSNF-000028 was also observed in NNMT knockout mice with diet-induced obesity, pointing towards the glucose-normalizing effect that may go beyond NNMT inhibition. JBSNF-000028 can be a potential therapeutic option for metabolic disorders and developmental studies are warranted.

Reagent-Controlled Divergent Synthesis of 2-Amino-1,3-Benzoxazines and 2-Amino-1,3-Benzothiazines.

A reagent-controlled chemoselective process has been devised for the synthesis of 4H-1,3-benzoxazines and related biologically important heterocycles in high yields under mild conditions. These scaffolds could be efficiently constructed using two different chemoselective reactions that rely on the choice of reagents and reaction conditions. The treatment of various 2-amino-arylalkyl alcohols with isothiocyanates afforded thiourea intermediates, which were reacted in situ with molecular iodine in the presence of triethylamine to give 2-amino-4H-1,3-benzoxazines, whereas the corresponding 2-amino-4H-1,3-benzothiazines were obtained by the reaction of thiourea intermediates in the presence of T3P (a mild cyclodehydrating agent) and triethylamine as the base. The described protocol represents the first example for the synthesis of 4H-1,3-benzoxazines via the dehydrosulfurization method using molecular iodine as the reagent.

A metal- and base-free domino protocol for the synthesis of 1,3-benzoselenazines, 1,3-benzothiazines and related scaffolds.

Efficient protocols have been described for the synthesis of 1,3-benzoselenazines, 1,3-benzothiazines, 2-aryl thiazin-4-ones and diaryl[b,f][1,5]diazocine-6,12(5H,11H)-diones. These transformations were successfully driven towards the product formation under mild acid catalyzed reaction conditions at room temperature using 2-amino aryl/hetero-aryl alkyl alcohols and amides as substrates. The merits of the present methods also rely on the easy access of rarely explored bioactive scaffolds like 1,3-benzoselenazine derivatives, for which well-documented methods are rarely known in the literature. A broad range of substrates with both electron-rich and electron-deficient groups were well-tolerated under the developed conditions to furnish the desired products in yields up to 98%. The scope of the devised method is not only restricted to the synthesis of 1,3-benzoselenazines, but it was also further extended towards the synthesis of 1,3-benzothiazines, 1,3-benzothiazinones and the corresponding eight membered N-heterocycles such as diaryl[b,f][1,5]diazocine-6,12(5H,11H)-diones.

Novel nicotinamide analog as inhibitor of nicotinamide N-methyltransferase.

Nicotinamide N-methyltransferase (NNMT) has been linked to obesity and diabetes. We have identified a novel nicotinamide (NA) analog, compound 12 that inhibited NNMT enzymatic activity and reduced the formation of 1-methyl-nicotinamide (MNA), the primary metabolite of NA by ∼80% at 2 h when dosed in mice orally at 50 mg/kg.