Discovery of novel, potent and orally efficacious inhibitor of neutral amino acid transporter B0AT1 (SLC6A19). (1st December 2021)

• Record Type: Journal Article
• Authors: Desai, Jigar; Patel, Bhaumin; Darji, Brijesh; Gite, Archana; Panchal, Nandini; Bhosale, Gokul; Shedage, Sandeep; Patel, Sandip; Kadam, Pravin; Patel, Gautam; Kumar Srivastava, Brijesh; Joharapurkar, Amit; Kshirsagar, Samadhan; Giri, Poonam; Bhayani, Hitesh; Patel, Ankit; Ghoshdastidar, Krishnarup; Bandyopadhyay, Debdutta; Kumar, Sanjay; Jain, Mukul; Sharma, Rajiv
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 53(2021)
• Publication Date: 2021-12-01
• Subjects: B0AT1 -- Nimesulide -- Nitro group -- Trifluoromethyl sulfonyl; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128421
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Inhibition of neutral amino acid transporter B 0 AT1 (SLC6A19) activity has been recently identified as promising strategy to treat type 2 diabetes and related disorders. Pharmacological inhibition of B 0 AT1 known to stimulate GLP1 and FGF21 in mice. This paper describes our efforts to discover first in class nanomolar potent B 0 AT1 inhibitor with excellent pharmacokinetics in mice. We have demonstrated animal efficacy data of lead B 0 AT1 inhibitor in diet induced obese (DIO) mice model. Abstract: Amino acid restriction by inhibition of neutral amino acid transporter, B 0 AT1 (SLC6A19) activity has been recently shown to improve glyceamic control by upregulating glucagon like peptide (GLP1) and fibroblast growth factor (FGF21) in mice. Hence, pharmacological inhibition of B 0 AT1 is expected to treat type-2 diabetes and related disorder. In this study, rationally designed trifluoromethyl sulfonyl derivatives were identified as novel, potent and orally bioavailable B 0 AT1 inhibitors. Compound 39 was found to be nanomolar potent (IC50 : 0.035 µM) B 0 AT1 inhibitor with excellent pharmacokinetic profile (%F: 66) in mice and efficacious in vivo in diet induced obese (DIO) mice model.