Discovery of Potent and Orally Bioavailable Small Molecule Antagonists of Toll-like Receptors 7/8/9 (TLR7/8/9)

Christopher P Mussari; Dharmpal S Dodd; Ratna Kumar Sreekantha; Laxman Pasunoori; Honghe Wan; Shana L Posy; David Critton; Stefan Ruepp; Murali Subramanian; Andrew Watson; Paul Davies; Gary L Schieven; Luisa M Salter-Cid; Ratika Srivastava; Debarati Mazumder Tagore; Shailesh Dudhgaonkar; Michael A Poss; Percy H Carter; Alaric J Dyckman

doi:10.1021/acsmedchemlett.0c00264

Discovery of Potent and Orally Bioavailable Small Molecule Antagonists of Toll-like Receptors 7/8/9 (TLR7/8/9)

ACS Med Chem Lett. 2020 Jul 29;11(9):1751-1758. doi: 10.1021/acsmedchemlett.0c00264. eCollection 2020 Sep 10.

Authors

Christopher P Mussari¹, Dharmpal S Dodd¹, Ratna Kumar Sreekantha², Laxman Pasunoori², Honghe Wan¹, Shana L Posy¹, David Critton¹, Stefan Ruepp¹, Murali Subramanian², Andrew Watson¹, Paul Davies¹, Gary L Schieven¹, Luisa M Salter-Cid¹, Ratika Srivastava², Debarati Mazumder Tagore², Shailesh Dudhgaonkar², Michael A Poss¹, Percy H Carter¹, Alaric J Dyckman¹

Affiliations

¹ Bristol Myers Squibb Research and Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
² The Biocon Bristol Myers Squibb Research Center (BBRC), Bangalore 560099, India.

Abstract

The toll-like receptor (TLR) family is an evolutionarily conserved component of the innate immune system, responsible for the early detection of foreign or endogenous threat signals. In the context of autoimmunity, the unintended recognition of self-motifs as foreign promotes initiation or propagation of disease. Overactivation of TLR7 and TLR9 have been implicated as factors contributing to autoimmune disorders such as psoriasis, arthritis, and lupus. In our search for small molecule antagonists of TLR7/9, 7f was identified as possessing excellent on-target potency for human TLR7/9 as well as for TLR8, with selectivity against other representative TLR family members. Good pharmacokinetic properties and a relatively balanced potency against TLR7 and TLR9 in mouse systems (systems which lack functional TLR8) made this an excellent in vivo tool compound, and efficacy from oral dosing in preclinical models of autoimmune disease was demonstrated.