Discovery of orally efficacious RORγt inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives

Kono, Mitsunori; Oda, Tsuneo; Tawada, Michiko; Imada, Takashi; Banno, Yoshihiro; Taya, Naohiro; Kawamoto, Tadashi; Tokuhara, Hidekazu; Tomata, Yoshihide; Ishii, Naoki; Ochida, Atsuko; Fukase, Yoshiyuki; Yukawa, Tomoya; Fukumoto, Shoji; Watanabe, Hiroyuki; Uga, Keiko; Shibata, Akira; Nakagawa, Hideyuki; Shirasaki, Mikio; Fujitani, Yasushi; Yamasaki, Masashi; Shirai, Junya; Yamamoto, Satoshi

doi:10.1016/j.bmc.2017.12.008

Cited by 20 publications

(18 citation statements)

References 32 publications

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“…Previously, Kono et al had already reported on the favorable in vitro RORγt and PK properties of 26. [71] The aim was to retain or improve the attractive biological profile as well as lower its lipophilicity, since it was non-optimal for drug delivery. The highly lipophilic trimethylsilyl group was swapped and cyclized to an indane ring.…”

Section: Cyclobutanes In Autoimmune Disease Researchmentioning

confidence: 99%

Cyclobutanes in Small‐Molecule Drug Candidates

Kolk¹,

Jansen²,

Rutjes³

et al. 2022

ChemMedChem

119

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Cyclobutanes are increasingly used in medicinal chemistry in the search for relevant biological properties. Important characteristics of the cyclobutane ring include its unique puckered structure, longer CÀ C bond lengths, increased CÀ C π-character and relative chemical inertness for a highly strained carbocycle. This review will focus on contributions of cyclobutane rings in drug candidates to arrive at favorable properties. Cyclobutanes have been employed for improving multiple factors such as preventing cis/trans-isomerization by replacing alkenes, replacing larger cyclic systems, increasing metabolic stability, directing key pharmacophore groups, inducing conformational restriction, reducing planarity, as aryl isostere and filling hydrophobic pockets.[a] M. R. van der Kolk, M.

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Section: Cyclobutanes In Autoimmune Disease Researchmentioning

confidence: 99%

Cyclobutanes in Small‐Molecule Drug Candidates

Kolk¹,

Jansen²,

Rutjes³

et al. 2022

ChemMedChem

119

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“…Efforts to discover orally bioavailable inverse agonists of RORγt, as an alternative to antibody treatment, have generated a variety of different structural classes. − Compounds affecting the receptor by binding to the LBD are not expected to exhibit isoform selectivity, because the two isoforms of RORγ differ only at their N-termini and share the same DNA- and ligand-binding domains. − Recent clinical candidates from these efforts include GNE-3500, GSK805, , GSK2981278, and VTP-43742 (Figure ). GSK2981278, whose structure has not been disclosed, was developed for the topical treatment of psoriasis but failed to show efficacy in a Phase 1 study, whereas Vitae Pharmaceuticals recently reported positive results for VTP-43742 from a Phase 2a study for the same indication.…”

Section: Introductionmentioning

confidence: 99%

Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design

Narjes¹,

Xue²,

Berg³

et al. 2018

J. Med. Chem.

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Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regulator of T17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-T17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.

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“…[51][52][53][54][55] On the other hand, the 5-substituted compounds are largely unexplored from this point of view, although some stimulating examples can be found in the literature. [56][57][58] The possibility to control stereochemistry in their synthesis will facilitate the exploration of their chemical space.…”

Section: Resultsmentioning

confidence: 99%