Rationally Designed, Conformationally Constrained Inverse Agonists of RORγt—Identification of a Potent, Selective Series with Biologic-Like in Vivo Efficacy

Abstract

RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.

Tricyclic-Carbocyclic RORγt Inverse Agonists—Discovery of BMS-986313

“…Compared to structure 2 (Figure ), the side chain amide nitrogen in the new series (compounds 3 – 7 ) is sterically hindered because it is attached to the tricyclic core, which could potentially alter or slow down metabolic processes such as N-dealkylation. Because the reverse amide series was a logical extension from our earlier tricyclic pyrrolidine series where the nitrogen atom was a part of the ring system, as illustrated in 1 , , a number of side chains studied earlier were re-examined here. Molecular modeling studies revealed that the trajectory of the side chains in both tricyclic pyrrolidine and reverse amide series point toward the RORγt polar pocket, consisting of a network of residues including Glu286, Leu287, Arg364, and Arg367.…”

“…85–23, revised 2011). Detailed biological experimental procedures, animal studies, and assay conditions used in this study can be found in our recent publications, refs . and .…”

Practical Synthesis of (3aR, 9bR)-8-Fluoro-7-(perfluoropropan-2-yl)-9b-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole: An Advanced Intermediate to Access the RORγt Inverse Agonist BMT-362265

“…Therefore, inverse agonists of RORγt have the potential for the treatment of a range of immune and inflammatory disorders. In continuation of our research in the same direction, , we recently reported a novel tricyclic RORγt inverse agonist, BMT-362265 , which was synthesized via coupling of the tricyclic core 10 with (1 R , 2 S , 4 R )-2-methylcyclohexane-1,4-dicarboxylic acid (Scheme ). This paper details an inexpensive, safer, and scalable synthetic route to the tricyclic core 10 of BMT-362265 .…”

Statistical Analysis of Protein-Ligand Interaction Patterns in Nuclear Receptor RORγ

“…We think that a statistical analysis of extensive structural information where one collectively examines protein-ligand contact interaction patterns may provide insight into this challenge. For this work, we studied 136 RORγ structures: 132 with one ligand (or ligand fragments) bound (100+ distinct ligands) from X-ray crystallography experiments ( Jin et al, 2010 ; Fujita-Sato et al, 2011 ; Fauber et al, 2013 ; Fauber et al, 2014 ; van Niel et al, 2014 ; Yang et al, 2014 ; Chao et al, 2015 ; Muegge et al, 2015 ; René et al, 2015 ; Santori et al, 2015 ; Scheepstra et al, 2015 ; Wang et al, 2015b ; Wang et al, 2015c ; Enyedy et al, 2016 ; Hirata et al, 2016 ; Hintermann et al, 2016 ; Marcotte et al, 2016 ; Olsson et al, 2016 ; Ouvry et al, 2016 ; Xue et al, 2016 ; Kallen et al, 2017 ; Kummer et al, 2017 ; Li et al, 2017 ; Noguchi et al, 2017 ; Carcache et al, 2018 ; Fukase et al, 2018 ; Gege et al, 2018 ; Gong et al, 2018 ; Kono et al, 2018 ; Narjes et al, 2018 ; Noguchi et al, 2018 ; Sasaki et al, 2018 ; Schnute et al, 2018 ; Shirai et al, 2018 ; Wang et al, 2018 ; Amaudrut et al, 2019 ; Duan et al, 2019 ; Hoegenauer et al, 2019 ; Kotoku et al, 2019 ; Lu et al, 2019 ; Marcoux et al, 2019 ; Sato et al, 2019 ; Strutzenberg et al, 2019 ; Tanis et al, 2019 ; von Berg et al, 2019 ; Yukawa et al, 2019 ; Zhang et al, 2019 ; Cherney et al, 2020 ; Duan et al, 2020 ; Gege et al, 2020 ; Harikrishnan et al, 2020 ; Jiang et al, 2020 ; Liu et al, 2020 ; Meijer et al, 2020 ;…”