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

Abstract

A series of tetrahydronaphthyridine derivatives as novel RORγt 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-({(5 R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORγt 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.

Cyclobutanes in Small‐Molecule Drug Candidates

“…This saturation increase also correlates to higher water solubility and lower melting points, both of which are key to successfully develop a lead compound [16] . Moreover, the cyclobutyl ring can be used to direct key pharmacophore groups, [17–22] fill a hydrophobic pocket in the target enzyme, [17,22–30] prevent cis / trans ‐isomerization, [31–33] improve metabolic stability, [34–36] replace aromatic groups as an aryl isostere, [37] conformationally restrict (part of) the molecule [38–41] or reduce planarity [42]…”

“…Multiple cyclobutane linked compounds were synthesized; the cis ‐1,4‐cyclobutane linker yielding compound 27 was optimal upon in vitro testing, while the lipophilicity was only slightly increased compared to the flexible linker. Compound 27 also showed the highest plasma exposure and oral bioavailability in in vivo studies in mice at 1 mg/kg [38] . This compound has undergone phase I clinical studies with no follows up as of now.…”

Molecular Mechanism of Action of RORγt Agonists and Inverse Agonists: Insights from Molecular Dynamics Simulation

“…The nuclear receptor (NR) retinoic acid receptor-related orphan receptor-gamma-t (RORγt, also known as NR1F3) is an important transcription factor involved in the differentiation of T helper 17 (Th17) cell and production of the pro-inflammatory cytokine, interleukin 17 (IL-17) [1]. The recent success of IL-17 antibodies (Secukinumab, Ixekizumab, and Brodalumab) and the progress of RORγt inverse agonists in clinical trials (VTP-43742, GSK2981278A, ARN-6039, TAK-828, ABBV-553, JNJ-3534, AZD-0284, JTE-451, JTE-151, RTA-1701) established that RORγt is a valuable drug-target for the treatment of autoimmune diseases [2,3,4,5,6,7,8]. Recent research has revealed that RORγt plays a critical role in the generation and function of Th17 and cytotoxic T (Tc17) cells [9,10,11,12,13].…”

Biochemical Properties of TAK-828F, a Potent and Selective Retinoid-Related Orphan Receptor Gamma t Inverse Agonist

“…According to their paper, TAK-828F binds to the LBD of RORγt, surrounded by amino acids of Phe377, Glu379, Arg364, Gln286, Phe388, and Gly380 [33]. It is well known that the activity of a nuclear receptor is regulated by various cofactor proteins.…”