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. 2023 Jan 18;14(2):191-198.
doi: 10.1021/acsmedchemlett.2c00500. eCollection 2023 Feb 9.

Macrocyclic Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonists

Mark E Schnute  1 , John I Trujillo  2 , Katherine L Lee  1 , Ray Unwalla  1 , Felix F Vajdos  2 , Björn Kauppi  3 , Philippe Nuhant  2 , Andrew C Flick  2 , Kimberly K Crouse  4 , Yajuan Zhao  4 , Amanda Samuel  5 , Vincent Lombardo  2 , Alexandria P Taylor  2 , Amy L Brault  2 , John D Knafels  2 , Michael L Vazquez  1 , Gabriel Berstein  4
Affiliations

Macrocyclic Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonists

Mark E Schnute et al. ACS Med Chem Lett. .

Abstract

Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound 14 demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Representative RORC2 inverse agonists that have entered human clinical trials delivered through oral dosing (1–4) or topical application (5).
Figure 2
Figure 2
Cocrystal structure of the RORC2 LBD with (a) compound 6 (8FAV) and (b) compound 7a (8FB1). Key residues in the binding pocket are labeled.
Figure 3
Figure 3
Cocrystal structure of the RORC2 LBD with compound 9 (8FB2). Key residues in the binding pocket are labeled.
Figure 4
Figure 4
In vitro permeation of topically applied compound 14 across human abdominal skin (5 donors, 10 replicates each; n = 50). Formulation: 2.75% (w/w) 14 in 30% (w/w) ethanol, 30% (w/w) PEG400, 20% (w/w) diethylene glycol monoethyl ether, 20% (w/w) glycerin. Error bars represent standard error of the mean. (a) Mean cumulative amount of 14 (ng/cm2) delivered to the receptor solution over a period of 24 h postapplication. (b) Mean concentration of 14 (μg/g) delivered to the epidermis and dermis 24 h postapplication.
Scheme 1
Scheme 1. Synthesis of Macrocycles 14–17
Reagents and conditions: (a) BnBr, K2CO3, DMF, 67%. (b) sec-BuLi, TMEDA, THF, CuCN, LiCl, allyl bromide, 43%. (c) 4 M HCl in dioxane, 96%. (d) Isobutyryl chloride, TEA, DCM, 97%. (e) 1-Chloroethyl carbonochloridate, DCE, MeOH, 25%. (f) 23, DCM, Na2SO4, NaBH(OAc)3, 54–61%. (g) Fe, H2O/MeOH (1:2), NH4Cl, 82–100%. (h) 3-Butene-1-sulfonyl chloride, THF, pyridine, 13–77%. (i) Grubbs Second Generation Catalyst, DCM, 21–61%. (j) PtO2, H2, 28–93%. (k) Chiral separation (SFC or HPLC).
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