Discovery of (&ITcis&IT-3-({(5&ITR&IT)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1&ITH&IT-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5&ITH&IT)-yl}carbonyl)cyclobutyl]acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

A series of tetrahydronaphthyridine derivatives as novel ROR gamma t inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower log D value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [cis-3-({(5R)-5-[(7-fluoro-1,1-dimethyl- 2,3-dihydro-1H-inden-5-yl) carbamoyl]-2-methoxyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl} carbonyl)-cyclobutyl] acetic acid, TAK-828F (10), which showed potent ROR gamma t inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound 10 exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound 10 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.