Discovery of 6-Oxo-4-phenyl-hexanoic acid derivatives as RORγt inverse agonists showing favorable ADME profile
| Autor: | Xiaoshan Min, Ryan White, Sanjay Singh, Anjan Chakrabarti, Jun Hirata, Ryota Nakajima, Tomohide Ida, Hiroyuki Oono, Antony Symons, Keiko Kumazawa, Zhulun Wang, Srinivasa Reddy Mothe, Angel Guzman-Perez, Satoshi Shuto, Sergei Belyakov |
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| Rok vydání: | 2020 |
| Předmět: |
Membrane permeability
Stereochemistry Clinical Biochemistry Retinoic acid Pharmaceutical Science 01 natural sciences Biochemistry chemistry.chemical_compound Mice Structure-Activity Relationship RAR-related orphan receptor gamma Drug Discovery Inverse agonist Animals Humans Molecular Biology Transcription factor Caproates ADME Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Nuclear Receptor Subfamily 1 Group F Member 3 Ligand (biochemistry) 0104 chemical sciences 010404 medicinal & biomolecular chemistry Nuclear receptor Microsomes Liver Molecular Medicine |
| Zdroj: | Bioorganicmedicinal chemistry letters. 36 |
| ISSN: | 1464-3405 |
| Popis: | The retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt), which is a promising therapeutic target for immune diseases, is a major transcription factor of genes related to psoriasis pathogenesis, such as interleukin (IL)-17A, IL-22, and IL-23R. Inspired by the co-crystal structure of RORγt, a 6-oxo-4-phenyl-hexanoic acid derivative 6a was designed, synthesized, and identified as a ligand of RORγt. The structure-activity relationship (SAR) studies in 6a, which focus on the improvement of its membrane permeability profile by introducing chlorine atoms, led to finding 12a, which has a potent RORγt inhibitory activity and a favorable pharmacokinetic profile. |
| Databáze: | OpenAIRE |
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