Small molecule amides as potent ROR-γ selective modulators

Department of Molecular Therapeutics and Translational Research Institute, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #A2A, Jupiter, FL 33458, USA.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.33). 11/2012; 23(2). DOI: 10.1016/j.bmcl.2012.11.025
Source: PubMed

ABSTRACT The structure-activity relationship study of a diphenylpropanamide series of ROR-γ selective modulators is reported. Compounds were screened using chimeric receptor Gal4 DNA-binding domain (DBD)-NR ligand binding domain cotransfection assay in a two-step format. Three different regions of the scaffold were modified to assess the effects on repression of ROR-γ transcriptional activity and potency. The lead compound 1 exhibits modest mouse pharmacokinetics and an acceptable in vitro profile which makes it a suitable in vivo probe to interrogate the functions of ROR-γ in animal models of disease.

Download full-text


Available from: Ruben Garcia, Jun 25, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nuclear receptors (NRs) are ligand-regulated transcription factors that regulate metabolism, development and immunity. The NR superfamily is one of the major classes of drug targets for human diseases. Retinoic acid receptor-related orphan receptor (ROR) α, β and γ belong to the NR superfamily, and these receptors are still considered as 'orphan' receptors because the identification of their endogenous ligands has been controversial. Recent studies have demonstrated that these receptors are regulated by synthetic ligands, thus emerge as important drug targets for the treatment of multiple sclerosis, rheumatoid arthritis, psoriasis, etc. Studying the structural basis and ligand development of RORs will pave the way for a better understanding of the roles of these receptors in human diseases. Here, we review the structural basis, disease relevance, strategies for ligand identification, and current status of development of therapeutic ligands for RORs.
    Acta Pharmacologica Sinica 12/2014; 36(1). DOI:10.1038/aps.2014.120 · 2.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: As the biology surrounding the nuclear receptor retinoic acid receptor-related orphan receptor gamma (RORγ or RORc) continues to evolve, significant effort has been invested in discovering modulators of this potentially important target for the treatment of metabolic and immunological diseases. Several major pharmaceutical and biotechnology companies have disclosed RORc inhibitors or partnered with other players in the field. In this perspective, we discuss both the biology and the underlying structural biology of RORc, and summarize the RORc modulators disclosed in the scientific and patent literature.
    Journal of Medicinal Chemistry 02/2014; 57(14). DOI:10.1021/jm401901d · 5.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The recent success reported in late-stage clinical trials for the treatment of psoriasis by antibodies directed against interleukin (IL)-17 or its receptor has validated and strongly supports the development of inhibitors of the IL-17 pathway as a new therapeutic modality in chronic inflammation and autoimmunity. These results also encourage the drug discovery of orally available small molecules that can modulate down the production of IL-17 by Th17 cells (the major IL-17 producers) or the downstream signaling of the IL-17 receptor. Here, we review these strategies with an emphasis on inhibiting the retinoic-acid-related orphan nuclear receptor RORγt, which is the master regulator of Th17 cells and a promising therapeutic target for the treatment of multiple autoimmune disorders.
    Drug discovery today 04/2014; 19(8). DOI:10.1016/j.drudis.2014.04.012 · 5.96 Impact Factor