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Letters in Drug Design & Discovery

Author(s): Maria A. Ortiz, Francisco J. Piedrafita, Ashley Bunnell and Adel Nefzi*

DOI: 10.2174/1570180820666230130093524

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Screening, Deconvolution and Parallel Synthesis of Trisubstituted Piperazine and Trisubstituted 2,3-diketopierazine Libraries for the Rapid Identification of Antagonists of the Nuclear Retinoic Acid Receptor-related Orphan Receptor Gamma (RORγ)

Page: [829 - 835] Pages: 7

  • * (Excluding Mailing and Handling)

Abstract

Background: Genetic studies support a key role for RORγ and RORα in the differentiation of proinflammatory Th17 cells, and a growing body of evidence suggests a pathogenic role for Th17 in several autoimmune diseases, including MS, rheumatoid arthritis, inflammatory bowel disease, type I diabetes, and psoriasis. RORγ antagonists have been shown to suppress Th17 differentiation and delay the onset of disease in an experimental autoimmune encephalomyelitis mouse model of MS.

Objective: Given the high therapeutic interest of RORγ antagonists and the promising activity of currently known ligands, small molecules with higher potency and receptor selectivity (in particular within the ROR family) are highly desirable. We used our small molecule compound library to discover, characterize, and optimize novel RORγ antagonists for the treatment of autoimmune diseases from Mixture-based Combinatorial Chemical Libraries.

Methods: We screened the FIU collection of small molecule libraries (>30 million compounds) composed of 75 molecular scaffolds systematically arranged in positional scanning and scaffold ranking formats. We identified scaffolds that selectively inhibit the binding of RORγ, RORγ, and RORβ but not RORα, and others that function as antagonists of all three receptors.

Results: The deconvolution of selected PS-SCL mixtures led to the identification of novel chemical entities, trisubstituted piperazine and diketopiperazine that function as RORγ antagonists.

Conclusion: The screening of a large complex library led to the rapid identification of novel trisubstituted piperazine and diketopiperazine antagonists of the nuclear retinoic acid receptor-related orphan receptor gamma (RORγ).

Graphical Abstract

[1]
Jetten, A.M.; Kurebayashi, S.; Ueda, E. The ROR nuclear orphan receptor subfamily: Critical regulators of multiple biological processes. Prog. Nucleic Acid Res. Mol. Biol., 2001, 69, 205-247.
[http://dx.doi.org/10.1016/S0079-6603(01)69048-2] [PMID: 11550795]
[2]
Jetten, A.M. Retinoid-related orphan receptors (RORs): Critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl. Recept. Signal., 2009, 7(1), nrs.07003.
[http://dx.doi.org/10.1621/nrs.07003] [PMID: 19381306]
[3]
Solt, L.A.; Griffin, P.R.; Burris, T.P. Ligand regulation of retinoic acid receptor-related orphan receptors: Implications for development of novel therapeutics. Curr. Opin. Lipidol., 2010, 21(3), 204-211.
[http://dx.doi.org/10.1097/MOL.0b013e328338ca18] [PMID: 20463469]
[4]
Yang, J.; Sundrud, M.S.; Skepner, J.; Yamagata, T. Targeting Th17 cells in autoimmune diseases. Trends Pharmacol. Sci., 2014, 35(10), 493-500.
[http://dx.doi.org/10.1016/j.tips.2014.07.006] [PMID: 25131183]
[5]
Pandya, V.B.; Kumar, S.; Sachchidanand, S.R.; Sharma, R.; Desai, R.C. Combating autoimmune diseases with retinoic acid receptor-related orphan receptor-γ (rorγ or rorc) inhibitors: Hits and misses. J. Med. Chem., 2018, 61(24), 10976-10995.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00588] [PMID: 30010338]
[6]
Bronner, S.M.; Zbieg, J.R.; Crawford, J.J. RORγ antagonists and inverse agonists: A patent review. Expert Opin. Ther. Pat., 2017, 27(1), 101-112.
[http://dx.doi.org/10.1080/13543776.2017.1236918] [PMID: 27629281]
[7]
Fauber, B.P.; Magnuson, S. Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc). J. Med. Chem., 2014, 57(14), 5871-5892.
[http://dx.doi.org/10.1021/jm401901d] [PMID: 24502334]
[8]
Kumar, N.; Solt, L.A.; Conkright, J.J.; Wang, Y.; Istrate, M.A.; Busby, S.A.; Garcia-Ordonez, R.D.; Burris, T.P.; Griffin, P.R. The benzenesulfoamide T0901317 [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] is a novel retinoic acid receptor-related orphan receptor-alpha/gamma inverse agonist. Mol. Pharmacol., 2010, 77(2), 228-236.
[http://dx.doi.org/10.1124/mol.109.060905] [PMID: 19887649]
[9]
Wang, Y.; Kumar, N.; Nuhant, P.; Cameron, M.D.; Istrate, M.A.; Roush, W.R.; Griffin, P.R.; Burris, T.P. Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ. ACS Chem. Biol., 2010, 5(11), 1029-1034.
[http://dx.doi.org/10.1021/cb100223d] [PMID: 20735016]
[10]
Jin, L.; Martynowski, D.; Zheng, S.; Wada, T.; Xie, W.; Li, Y. Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma. Mol. Endocrinol., 2010, 24(5), 923-929.
[http://dx.doi.org/10.1210/me.2009-0507] [PMID: 20203100]
[11]
Huh, J.R.; Leung, M.W.L.; Huang, P.; Ryan, D.A.; Krout, M.R.; Malapaka, R.R.V.; Chow, J.; Manel, N.; Ciofani, M.; Kim, S.V.; Cuesta, A.; Santori, F.R.; Lafaille, J.J.; Xu, H.E.; Gin, D.Y.; Rastinejad, F.; Littman, D.R. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity. Nature, 2011, 472(7344), 486-490.
[http://dx.doi.org/10.1038/nature09978] [PMID: 21441909]
[12]
Solt, L.A.; Kumar, N.; Nuhant, P.; Wang, Y.; Lauer, J.L.; Liu, J.; Istrate, M.A.; Kamenecka, T.M.; Roush, W.R. Vidović, D.; Schürer, S.C.; Xu, J.; Wagoner, G.; Drew, P.D.; Griffin, P.R.; Burris, T.P. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature, 2011, 472(7344), 491-494.
[http://dx.doi.org/10.1038/nature10075] [PMID: 21499262]
[13]
Xu, T.; Wang, X.; Zhong, B.; Nurieva, R.I.; Ding, S.; Dong, C. Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORgamma t protein. J. Biol. Chem., 2011, 286(26), 22707-22710.
[http://dx.doi.org/10.1074/jbc.C111.250407] [PMID: 21566134]
[14]
Kumar, N.; Lyda, B.; Chang, M.R.; Lauer, J.L.; Solt, L.A.; Burris, T.P.; Kamenecka, T.M.; Griffin, P.R. Identification of SR2211: A potent synthetic RORγ-selective modulator. ACS Chem. Biol., 2012, 7(4), 672-677.
[http://dx.doi.org/10.1021/cb200496y] [PMID: 22292739]
[15]
Solt, L.A.; Kumar, N.; He, Y.; Kamenecka, T.M.; Griffin, P.R.; Burris, T.P. Identification of a selective RORγ ligand that suppresses T(H)17 cells and stimulates T regulatory cells. ACS Chem. Biol., 2012, 7(9), 1515-1519.
[http://dx.doi.org/10.1021/cb3002649] [PMID: 22769242]
[16]
Huh, J.R.; Englund, E.E.; Wang, H.; Huang, R.; Huang, P.; Rastinejad, F.; Inglese, J.; Austin, C.P.; Johnson, R.L.; Huang, W.; Littman, D.R. Identification of potent and selective diphenylpropanamide rorγ inhibitors. ACS Med. Chem. Lett., 2013, 4(1), 79-84.
[http://dx.doi.org/10.1021/ml300286h] [PMID: 24040486]
[17]
Capone, A.; Volpe, E. Transcriptional regulators of t helper 17 cell differentiation in health and autoimmune diseases. Front. Immunol., 2020, 11, 348.
[http://dx.doi.org/10.3389/fimmu.2020.00348] [PMID: 32226427]
[18]
Eberl, G. RORγt, a multitask nuclear receptor at mucosal surfaces. Mucosal Immunol., 2017, 10(1), 27-34.
[http://dx.doi.org/10.1038/mi.2016.86] [PMID: 27706126]
[19]
Zou, H.; Yang, N.; Zhang, X.; Chen, H.W. RORγ is a context-specific master regulator of cholesterol biosynthesis and an emerging therapeutic target in cancer and autoimmune diseases. Biochem. Pharmacol., 2022, 196, 114725.
[http://dx.doi.org/10.1016/j.bcp.2021.114725] [PMID: 34384758]
[20]
Sun, N.; Guo, H.; Wang, Y. Retinoic acid receptor-related orphan receptor gamma-t (RORγt) inhibitors in clinical development for the treatment of autoimmune diseases: A patent review (2016-present). Expert Opin. Ther. Pat., 2019, 29(9), 663-674.
[http://dx.doi.org/10.1080/13543776.2019.1655541] [PMID: 31403347]
[21]
Nefzi, A.; Giulianotti, M.A.; Houghten, R.A. Solid-phase synthesis of substituted 2,3-diketopiperazines from reduced polyamides. Tetrahedron, 2000, 56(21), 3319-3326.
[http://dx.doi.org/10.1016/S0040-4020(00)00253-2]
[22]
Nefzi, A.; Ostresh, J.M.; Yu, J.; Houghten, R.A. Combinatorial chemistry: Libraries from libraries, the art of the diversity-oriented transformation of resin-bound peptides and chiral polyamides to low molecular weight acyclic and heterocyclic compounds. J. Org. Chem., 2004, 69(11), 3603-3609.
[http://dx.doi.org/10.1021/jo040114j] [PMID: 15152987]
[23]
Nefzi, A.; Mimna, R.A.; Houghten, R.A. Parallel solid-phase synthesis of disubstituted 1,6-piperazine-2-ones. J. Comb. Chem., 2002, 4(6), 542-545.
[http://dx.doi.org/10.1021/cc0200235] [PMID: 12425596]
[24]
Rohde, K.H.; Michaels, H.A.; Nefzi, A. Synthesis and antitubercular activity of 1,2,4-trisubstitued piperazines. Bioorg. Med. Chem. Lett., 2016, 26(9), 2206-2209.
[http://dx.doi.org/10.1016/j.bmcl.2016.03.063] [PMID: 27020522]
[25]
Houghten, R.A. General method for the rapid solid-phase synthesis of large numbers of peptides: Specificity of antigen-antibody interaction at the level of individual amino acids. Proc. Natl. Acad. Sci. USA, 1985, 82(15), 5131-5135.
[http://dx.doi.org/10.1073/pnas.82.15.5131] [PMID: 2410914]
[26]
Ortiz, M.A.; Piedrafita, F.J.; Nefzi, A. 1,5-disubstituted acylated 2-amino-4,5-dihydroimidazoles as a new class of retinoic acid receptor–related orphan receptor (ROR) inhibitors. Int. J. Mol. Sci., 2022, 23(8), 4433.
[http://dx.doi.org/10.3390/ijms23084433] [PMID: 35457251]
[27]
Nefzi, A.; Marconi, G.D.; Ortiz, M.A.; Davis, J.C.; Piedrafita, F.J. Synthesis of dihydroimidazole tethered imidazolinethiones and their activity as novel antagonists of the nuclear retinoic acid receptor-related orphan receptors (RORs). Bioorg. Med. Chem. Lett., 2017, 27(7), 1608-1610.
[http://dx.doi.org/10.1016/j.bmcl.2017.02.014] [PMID: 28242276]
[28]
Wu, J.; Zhang, Y.; Maida, L.E.; Santos, R.G.; Welmaker, G.S.; LaVoi, T.M.; Nefzi, A.; Yu, Y.; Houghten, R.A.; Toll, L.; Giulianotti, M.A. Scaffold ranking and positional scanning utilized in the discovery of nAChR-selective compounds suitable for optimization studies. J. Med. Chem., 2013, 56(24), 10103-10117.
[http://dx.doi.org/10.1021/jm401543h] [PMID: 24274400]
[29]
Al-Ali, H.; Debevec, G.; Santos, R.G.; Houghten, R.A.; Davis, J.C.; Nefzi, A.; Lemmon, V.P.; Bixby, J.L.; Giulianotti, M.A. Scaffold ranking and positional scanning identify novel neurite outgrowth promoters with nanomolar potency. ACS Med. Chem. Lett., 2018, 9(10), 1057-1062.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00425] [PMID: 30344917]
[30]
Perry, D., Jr; Roberts, B.; Debevec, G.; Michaels, H.; Chakrabarti, D.; Nefzi, A. Identification of bis-cyclic guanidines as antiplasmodial compounds from positional scanning mixture-based libraries. Molecules, 2019, 24(6), 1100.
[http://dx.doi.org/10.3390/molecules24061100] [PMID: 30897744]
[31]
Stefanovic, B.; Michaels, H.A.; Nefzi, A. Discovery of a lead compound for specific inhibition of type i collagen production in fibrosis. ACS Med. Chem. Lett., 2021, 12(3), 477-484.
[http://dx.doi.org/10.1021/acsmedchemlett.1c00006] [PMID: 33738075]
[32]
Hoesl, C.E.; Ostresh, J.M.; Houghten, R.A.; Nefzi, A. Solid phase synthesis of novel 3,4,7-trisubstituted 4,5,8,9-tetrahydro-3H-imidazo[1,2-a] [1,3,5] triazepin-2(7H)-thiones and N-alkyl-4,5,7,8-tetrahydro-3H-imidazo[1,2-a] [1,3,5] tria-zepin-2-amines. J. Comb. Chem., 2006, 8(1), 127-131.
[http://dx.doi.org/10.1021/cc050094e] [PMID: 16398563]
[33]
Pinilla, C.; Appel, J.R.; Blanc, P.; Houghten, R.A. Rapid identification of high affinity peptide ligands using positional scanning synthetic peptide combinatorial libraries. Biotechniques, 1992, 13(6), 901-905.
[PMID: 1476743]
[34]
Chesnokov, O.; Visitdesotrakul, P.; Kalani, K.; Nefzi, A.; Oleinikov, A.V. Small molecule compounds identified from mixture-based library inhibit binding between plasmodium falciparum infected erythrocytes and endothelial receptor ICAM-1. Int. J. Mol. Sci., 2021, 22(11), 5659.
[http://dx.doi.org/10.3390/ijms22115659] [PMID: 34073419]
[35]
Houghten, R.A.; Pinilla, C.; Appel, J.R.; Blondelle, S.E.; Dooley, C.T.; Eichler, J.; Nefzi, A.; Ostresh, J.M. Mixture-based synthetic combinatorial libraries. J. Med. Chem., 1999, 42(19), 3743-3778.
[http://dx.doi.org/10.1021/jm990174v] [PMID: 10508425]