Substituted diaryl ether compounds as retinoic acid-related orphan Receptor-γt (RORγt) agonists

Zheming Ruan; Peter K Park; Donna Wei; Ashok Purandare; Honghe Wan; Daniel O'Malley; Sylwia Stachura; Heidi Perez; Cullen L Cavallaro; 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; Jenny H Xie; Monique Anthony; Michele Agler; Brian E Fink; Lalgudi S Harikrishnan

doi:10.1016/j.bmcl.2021.127778

Substituted diaryl ether compounds as retinoic acid-related orphan Receptor-γt (RORγt) agonists

Bioorg Med Chem Lett. 2021 Mar 1:35:127778. doi: 10.1016/j.bmcl.2021.127778. Epub 2021 Jan 8.

Authors

Zheming Ruan¹, Peter K Park², Donna Wei², Ashok Purandare², Honghe Wan², Daniel O'Malley², Sylwia Stachura², Heidi Perez², Cullen L Cavallaro², 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, Jenny H Xie⁷, Monique Anthony⁵, Michele Agler⁵, Brian E Fink², Lalgudi S Harikrishnan²

Affiliations

¹ Department of Chemistry, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA. Electronic address: [email protected].
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, 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: 33422603
DOI: 10.1016/j.bmcl.2021.127778

Abstract

The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.

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

MeSH terms

Animals
Crystallography, X-Ray
Dose-Response Relationship, Drug
Ethers / chemical synthesis
Ethers / chemistry
Ethers / pharmacology*
Humans
Mice
Models, Molecular
Molecular Structure
Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
Structure-Activity Relationship
Th17 Cells
Tretinoin / chemical synthesis
Tretinoin / chemistry
Tretinoin / pharmacology*

Substances

Ethers
Nuclear Receptor Subfamily 1, Group F, Member 3
Tretinoin