Substituted benzyloxytricyclic compounds as retinoic acid-related orphan receptor gamma t (RORγt) agonists

Lalgudi S Harikrishnan; Patrice Gill; Muthoni G Kamau; Lan-Ying Qin; Zheming Ruan; Daniel O'Malley; Tram Huynh; Sylwia Stachura; Cullen L Cavallaro; Zhonghui Lu; James J-W Duan; Carolyn A Weigelt; John S Sack; Max Ruzanov; Javed Khan; Murali Gururajan; Jessica J Wong; Yanling Huang; Melissa Yarde; Zhuyin Li; Cliff Chen; Huadong Sun; Virna Borowski; Anwar Murtaza; Brian E Fink

doi:10.1016/j.bmcl.2020.127204

Substituted benzyloxytricyclic compounds as retinoic acid-related orphan receptor gamma t (RORγt) agonists

Bioorg Med Chem Lett. 2020 Jun 15;30(12):127204. doi: 10.1016/j.bmcl.2020.127204. Epub 2020 Apr 20.

Authors

Lalgudi S Harikrishnan¹, Patrice Gill², Muthoni G Kamau², Lan-Ying Qin², Zheming Ruan², Daniel O'Malley², Tram Huynh², Sylwia Stachura², Cullen L Cavallaro², Zhonghui Lu², James J-W Duan², Carolyn A Weigelt³, John S Sack³, Max Ruzanov³, Javed Khan³, Murali Gururajan⁴, Jessica J Wong⁴, Yanling Huang⁴, Melissa Yarde⁵, Zhuyin Li⁵, Cliff Chen⁶, Huadong Sun⁶, Virna Borowski⁷, Anwar Murtaza⁷, Brian E Fink²

Affiliations

¹ Department of Chemistry, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA. Electronic address: lalgudi.harikrishnan@bms.com.
² Department of Chemistry, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA.
³ Molecular Structure & Design, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA.
⁴ Immuno-Oncology Small Molecule Biology, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA.
⁵ Lead Discovery & Optimization, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA.
⁶ Preclinical Candidate Optimization, MAP, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA.
⁷ In vivo Pharmacology, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA.

PMID: 32334911
DOI: 10.1016/j.bmcl.2020.127204

Abstract

Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.

Keywords: ROR gamma; RORgt; RORγt; Retinoic acid related orphan receptor; TH17 cells and IL-17.

MeSH terms

Animals
Benzyl Compounds / chemistry
Benzyl Compounds / pharmacology*
Dose-Response Relationship, Drug
Female
Heterocyclic Compounds / chemistry
Heterocyclic Compounds / pharmacology*
Mice
Mice, Inbred C57BL
Molecular Structure
Receptors, Retinoic Acid / agonists*
Retinoic Acid Receptor gamma
Structure-Activity Relationship

Substances

Benzyl Compounds
Heterocyclic Compounds
Receptors, Retinoic Acid