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

Bioorganic & medicinal chemistry letters 2021 Dec 01

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Amino acid restriction by inhibition of neutral amino acid transporter, B0AT1 (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 B0AT1 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 B0AT1 inhibitors. Compound 39 was found to be nanomolar potent (IC50: 0.035 µM) B0AT1 inhibitor with excellent pharmacokinetic profile (%F: 66) in mice and efficacious in vivo in diet induced obese (DIO) mice model. Copyright © 2021 Elsevier Ltd. All rights reserved.

Citation

Jigar Desai, Bhaumin Patel, Brijesh Darji, Archana Gite, Nandini Panchal, Gokul Bhosale, Sandeep Shedage, Sandip Patel, Pravin Kadam, Gautam Patel, Brijesh Kumar Srivastava, Amit Joharapurkar, Samadhan Kshirsagar, Poonam Giri, Hitesh Bhayani, Ankit Patel, Krishnarup Ghoshdastidar, Debdutta Bandyopadhyay, Sanjay Kumar, Mukul Jain, Rajiv Sharma. Discovery of novel, potent and orally efficacious inhibitor of neutral amino acid transporter B0AT1 (SLC6A19). Bioorganic & medicinal chemistry letters. 2021 Dec 01;53:128421