Bioorganic & medicinal chemistry letters · 2021
Discovery of novel, potent and orally efficacious inhibitor of neutral amino acid transporter B0AT1 (SLC6A19).
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.