Discovery of novel, potent and orally efficacious inhibitor of neutral amino acid transporter B 0 AT1 (SLC6A19)

Amino acid restriction by inhibition of neutral amino acid transporter, B 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 AT1 is expected to t...

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Published inBioorganic & medicinal chemistry letters Vol. 53; p. 128421
Main 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
Format Journal Article
LanguageEnglish
Published England 01.12.2021
Subjects
Amino Acid Transport Systems, Neutral - antagonists & inhibitors
Amino Acid Transport Systems, Neutral - metabolism
Animals
Anti-Inflammatory Agents, Non-Steroidal - chemistry
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Dose-Response Relationship, Drug
Drug Discovery
Mice
Mice, Inbred C57BL
Molecular Structure
Structure-Activity Relationship
Sulfonamides - chemistry
Sulfonamides - pharmacology
Nitro group
BAT1
Trifluoromethyl sulfonyl
Nimesulide
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Summary:Amino acid restriction by inhibition of neutral amino acid transporter, B 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 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 AT1 inhibitors. Compound 39 was found to be nanomolar potent (IC : 0.035 µM) B AT1 inhibitor with excellent pharmacokinetic profile (%F: 66) in mice and efficacious in vivo in diet induced obese (DIO) mice model.
ISSN:1464-3405