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

doi:10.1016/j.bmcl.2019.06.044

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

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2208-2217. doi: 10.1016/j.bmcl.2019.06.044. Epub 2019 Jun 22.

Authors

Nadim S Shaikh¹, Jitesh P Iyer², Yogesh S Munot², Partha P Mukhopadhyay², Amol A Raje², Ranganayaki Nagaraj², Vijay Jamdar², Ravindra Gavhane², Mahendra Lohote², Prasad Sherkar², Madhu Bala², Rajkanth Petla², Ashwinkumar Meru², Dhananjay Umrani², Sreekanth Rouduri², Sachin Joshi², Satyanarayan Reddy², Vishwottam Kandikere², Debnath Bhuniya², Bheemashankar Kulkarni², Kasim A Mookhtiar²

Affiliations

¹ Drug Discovery Facility - Pune, Advinus Therapeutics Limited, Head Office: Block No. 21 & 22, Phase II, Peenya Industrial Area, Bangalore 560058, India. Electronic address: nadims123@gmail.com.
² Drug Discovery Facility - Pune, Advinus Therapeutics Limited, Head Office: Block No. 21 & 22, Phase II, Peenya Industrial Area, Bangalore 560058, India.

PMID: 31272795
DOI: 10.1016/j.bmcl.2019.06.044

Abstract

Targeting nuclear receptor RORγ is recognized to be beneficial in multiple autoimmune disorders. We disclosed new indole analogues as potent RORγ inverse agonists. RO-2 as one of the potent and orally bioavailable compounds was evaluated in various models of autoimmune disorder. It showed potent suppression of downstream markers of RORγt activity in murine and human primary cells, ex vivo PD assay and in multiple animal models of autoimmune diseases. The results indicate the potential of these indole analogues as orally bioavailable small molecule inverse agonists of RORγt, efficacious in various Th17 driven models of autoimmune disorders.

Keywords: Autoimmune diseases; IL-17; Indole; Psoriasis; RORc; RORγ.

Publication types

Letter
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoimmune Diseases / drug therapy*
Humans
Indoles / chemistry*
Mice
Models, Molecular
Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
Structure-Activity Relationship

Substances

Indoles
Nuclear Receptor Subfamily 1, Group F, Member 3
RORC protein, human