Novel Pyrimidine-5-carboxamide Compounds as NNMT Inhibitors for Treating Diabetes.

pubs.acs.org/acsmedchemlett Patent Highlight Novel Pyrimidine-5-carboxamide Compounds as NNMT Inhibitors for Treating Diabetes Ram W. Sabnis* Cite This: ACS Med. Chem. Lett. 2021, 12, 538−539 ACCESS Read Online Metrics & More Article Recommendations Important Compound Classes. The present application describes a series of novel pyrimidine5-carboxamide compounds as NNMT inhibitors for the treatment of diabetes, metabolic syndrome, and chronic kidney disease. Further, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment. Definitions. R = cyclopropyl and geminal cyclopropyl. Key Structures. Title. Pyrimidine-5-carboxamide Compound Patent Publication Number. WO 2021/025975 A1 Publication Date. February 11, 2021 Priority Application. EP 19382686.4 and EP 19382744.1 Priority Date. August 6, 2019 and September 2, 2019 Inventors. Ruenoplaza, G. Assignee Company. Eli Lilly and Company, USA Disease Area. Diabetes Biological Target. Nicotinamide N-methyltransferase (NNMT) Summary. Nicotinamide N-methyltransferase (NNMT) is an enzyme that catalyzes the transfer of a methyl group from the universal methyl donor S-(5′-adenosyl)-L-methionine (SAM) onto nicotinamide (NAM), resulting in the formation of 1methylnicotinamide (1-MeNAM). NNMT is a potential therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Analogues of nicotinamide have been reported as NNMT inhibitors. Small molecule inhibitors of NNMT for treating metabolic disorders are described. NNMT inhibitors which are efficacious and orally bioavailable are desired. Increased expression and activity of NNMT has been linked to various disease pathologies including metabolic syndrome, cardiovascular disease, neurodegeneration, and cancer. Of particular interest is the correlation exhibited between adipose NNMT activity and insulin resistance. This mechanism appears to be reversible, as adipose NNMT activity was reduced following interventions that improve insulin resistance. Genetic knockdown of the NNMT gene in mice showed protective effects against diet-induced obesity, and the animals displayed enhanced insulin sensitization, validating its potential utility as a therapeutic target for metabolic disorder and type 2 diabetes mellitus. Amelioration of hyperhomocysteinemia in these patients, via NNMT inhibition may serve as a valuable therapeutic mechanism for the treatment of chronic kidney disease (CKD). Published 2021 by American Chemical Society Biological Assay. The biochemical NNMT inhibition assay in human and mouse was performed. The compounds described in this application were tested for their ability to inhibit NNMT. The NNMT IC50 (nM) are shown in the following table. Biological Data. The table below shows representative compounds were tested for NNMT inhibition. The biological Received: March 13, 2021 Published: March 26, 2021 538 https://doi.org/10.1021/acsmedchemlett.1c00150 ACS Med. Chem. Lett. 2021, 12, 538−539 ACS Medicinal Chemistry Letters pubs.acs.org/acsmedchemlett Patent Highlight data obtained from testing representative examples are listed in the following table. Claims. Total claims: 21 Compound claims: 9 Pharmaceutical composition claims: 1 Method of treatment claims: 7 Use of compound claims: 4 Recent Review Articles. 1. Fan, L.; Cacicedo, J. M.; Ido, Y. J. Diabetes Invest. 2020, 11, 1403. 2. Roberti, A.; Fernandez, A. F.; Fraga, M. F. Mol. Metab. 2021, 45, 101165. 3. Amjad, S.; Nisar, S.; Bhat, A. A.; Shah, A. R.; Frenneaux, M. P.; Fakhro, K.; Haris, M.; Reddy, R.; Patay, Z.; Baur, J.; Bagga, P. Mol. Metab. 2021, 49, 101195. 4. Chandra, S.; Srinivasan, S.; Batra, J. Cancer Med. 2021, 10, 1791. 5. Tang, Z.; Xu, Z.; Zhu, X.; Zhang, J. Cancer Commun. 2021, 41, 16. ■ AUTHOR INFORMATION Corresponding Author Ram W. Sabnis − Smith, Gambrell & Russell LLP, Atlanta, Georgia 30309, United States; orcid.org/0000-00017289-0581; Email: Complete contact information is available at: https://pubs.acs.org/10.1021/acsmedchemlett.1c00150 Notes The author declares no competing financial interest. 539 https://doi.org/10.1021/acsmedchemlett.1c00150 ACS Med. Chem. Lett. 2021, 12, 538−539  (...truncated)