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. 2013 Jan 15;23(2):532-6.
doi: 10.1016/j.bmcl.2012.11.025. Epub 2012 Nov 22.

Small molecule amides as potent ROR-γ selective modulators

Pasha M Khan  1 , Bahaa El-Dien M El-Gendy, Naresh Kumar, Ruben Garcia-Ordonez, Li Lin, Claudia H Ruiz, Michael D Cameron, Patrick R Griffin, Theodore M Kamenecka
Affiliations

Small molecule amides as potent ROR-γ selective modulators

Pasha M Khan et al. Bioorg Med Chem Lett. .

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.

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Figures

Figure 1
Figure 1
SR-9805 (1) and analogs as ROR-γ modulators
Figure 2
Figure 2
Demonstration of transcriptional repression and binding of compound 1 to RORγ.
Scheme 1
Scheme 1
Reagents and conditions: a. TFA, µW, 30 min, 120 °C; b. R1R2NH, THF, 60 °C, 2h.
Scheme 2
Scheme 2
Reagents and Conditions: a. DCC, DMF, µW, 30 min, 120 °C; b. (1) H2, Pd-C, 48h, (2) 3,5-Dimethylpiperidine, THF, 40 °C. (c) NaI, TMSCl, DMF, 140 °C; (d) 3,5-Dimethylpiperidine, THF, 40 °C
See this image and copyright information in PMC

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