Discovery and pharmacological evaluation of indole derivatives as potent and selective RORγt inverse agonist for multiple autoimmune conditions.

Nadim S Shaikh, Jitesh P Iyer, Yogesh S Munot, Partha P Mukhopadhyay,Amol A Raje, Ranganayaki Nagaraj, Vijay Jamdar, Ravindra Gavhane, Mahendra Lohote,Prasad Sherkar,Madhu Bala,Rajkanth Petla,Ashwinkumar Meru,Dhananjay Umrani,Sreekanth Rouduri,Sachin Joshi, Satyanarayan Reddy,Vishwottam Kandikere,Debnath Bhuniya, Bheemashankar Kulkarni,Kasim A Mookhtiar

Bioorganic & Medicinal Chemistry Letters(2019)

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摘要
•Identification of indole analogues as potent RORγt inverse agonists, SAR of around 44 compounds is presented.•Potent compounds were evaluated for pharmacokinetic properties and data is presented.•Significant inhibition of anti-CD3/anti-CD28 induced Il17 gene expression in mouse splenocytes assay.•One of the potent compounds, RO-2 inhibited IL-17A release from (a) mouse splenocytes and (b) human whole blood with an IC50 of 503 nM and 490 nM respectively.•RO-2 was evaluated for its potential in experimental autoimmune encephalomyelitis (EAE) and psoriasis model.
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