Identification of Potent RORβ Modulators: Scaffold Variation

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2018 Aug 26

PMID 30143422

Authors

Christelle Doebelin

Remi Patouret

Ruben D Garcia-Ordonez

Mi Ra Chang

Venkatasubramanian Dharmarajan

Scott Novick

Anthony Ciesla

Sean Campbell

Laura A Solt

Patrick R Griffin

Theodore M Kamenecka

Affiliations

Soon will be listed here.

Abstract

We sought to develop RORβ-selective probe molecules in order to investigate the function of the receptor in vitro and in vivo and its role in the pathophysiology of disease. To accomplish this, we modified a potent dual RORβ/RORγ inverse agonist from the primary literature with the goal of improving selectivity for RORβ vs RORγ. Truncation of the Western portion of the molecule ablated activity at RORγ and led to a potent series of RORβ modulators. Continued exploration of this series investigated alternate replacement cores for the aminothiazole ring. Numerous suitable replacements were found during the course of our SAR investigations and are reported herein.

References

Jia L, Oh E, Ng L, Srinivas M, Brooks M, Swaroop A . Retinoid-related orphan nuclear receptor RORbeta is an early-acting factor in rod photoreceptor development. Proc Natl Acad Sci U S A. 2009; 106(41):17534-9. PMC: 2765160. DOI: 10.1073/pnas.0902425106. View

Scheepstra M, Leysen S, van Almen G, Richard Miller J, Piesvaux J, Kutilek V . Identification of an allosteric binding site for RORγt inhibition. Nat Commun. 2015; 6:8833. PMC: 4686831. DOI: 10.1038/ncomms9833. View

Gege C, Schluter T, Hoffmann T . Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORβ and RORγt. Bioorg Med Chem Lett. 2014; 24(22):5265-7. DOI: 10.1016/j.bmcl.2014.09.053. View

McClung C . Circadian genes, rhythms and the biology of mood disorders. Pharmacol Ther. 2007; 114(2):222-32. PMC: 1925042. DOI: 10.1016/j.pharmthera.2007.02.003. View

Steinmayr M, Andre E, Conquet F, Rondi-Reig L, Delhaye-Bouchaud N, Auclair N . staggerer phenotype in retinoid-related orphan receptor alpha-deficient mice. Proc Natl Acad Sci U S A. 1998; 95(7):3960-5. PMC: 19945. DOI: 10.1073/pnas.95.7.3960. View

Gibson C, Schnatbaum K, Pfeifer J, Locardi E, Paschke M, Reimer U . Novel small molecule bradykinin B2 receptor antagonists. J Med Chem. 2009; 52(14):4370-9. DOI: 10.1021/jm9002445. View

Shalinsky D, Bischoff E, Lamph W, Zhang L, Boehm M, Davies P . A novel retinoic acid receptor-selective retinoid, ALRT1550, has potent antitumor activity against human oral squamous carcinoma xenografts in nude mice. Cancer Res. 1997; 57(1):162-8. View

Hamilton B, Frankel W, Kerrebrock A, HAWKINS T, Fitzhugh W, Kusumi K . Disruption of the nuclear hormone receptor RORalpha in staggerer mice. Nature. 1996; 379(6567):736-9. DOI: 10.1038/379736a0. View

Roforth M, Liu G, Khosla S, Monroe D . Examination of nuclear receptor expression in osteoblasts reveals Rorβ as an important regulator of osteogenesis. J Bone Miner Res. 2011; 27(4):891-901. PMC: 3667501. DOI: 10.1002/jbmr.1502. View

10.

Stehlin C, Wurtz J, Steinmetz A, Greiner E, Schule R, Moras D . X-ray structure of the orphan nuclear receptor RORbeta ligand-binding domain in the active conformation. EMBO J. 2001; 20(21):5822-31. PMC: 125710. DOI: 10.1093/emboj/20.21.5822. View

11.

Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud J . All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta. Nat Struct Biol. 2003; 10(10):820-5. DOI: 10.1038/nsb979. View

12.

Wang Y, Cai W, Zhang G, Yang T, Liu Q, Cheng Y . Discovery of novel N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides as potent RORγt inhibitors. Bioorg Med Chem. 2014; 22(2):692-702. DOI: 10.1016/j.bmc.2013.12.021. View

13.

Miller S, Weinmann A . Common themes emerge in the transcriptional control of T helper and developmental cell fate decisions regulated by the T-box, GATA and ROR families. Immunology. 2009; 126(3):306-15. PMC: 2669811. DOI: 10.1111/j.1365-2567.2008.03040.x. View

14.

Lai Y, Kao C, Lu M, Chen H, Chen P, Chen C . Investigation of associations between NR1D1, RORA and RORB genes and bipolar disorder. PLoS One. 2015; 10(3):e0121245. PMC: 4366256. DOI: 10.1371/journal.pone.0121245. View

15.

Medvedev A, Yan Z, Hirose T, Giguere V, Jetten A . Cloning of a cDNA encoding the murine orphan receptor RZR/ROR gamma and characterization of its response element. Gene. 1996; 181(1-2):199-206. DOI: 10.1016/s0378-1119(96)00504-5. View

16.

Mansour H, Monk T, Nimgaonkar V . Circadian genes and bipolar disorder. Ann Med. 2005; 37(3):196-205. DOI: 10.1080/07853890510007377. View

17.

Rudolf G, Lesca G, Mehrjouy M, Labalme A, Salmi M, Bache I . Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy. Eur J Hum Genet. 2016; 24(12):1761-1770. PMC: 5117930. DOI: 10.1038/ejhg.2016.80. View

18.

Fauber B, Rene O, De Leon Boenig G, Burton B, Deng Y, Eidenschenk C . Reduction in lipophilicity improved the solubility, plasma-protein binding, and permeability of tertiary sulfonamide RORc inverse agonists. Bioorg Med Chem Lett. 2014; 24(16):3891-7. DOI: 10.1016/j.bmcl.2014.06.048. View

19.

Masana M, Sumaya I, Becker-Andre M, Dubocovich M . Behavioral characterization and modulation of circadian rhythms by light and melatonin in C3H/HeN mice homozygous for the RORbeta knockout. Am J Physiol Regul Integr Comp Physiol. 2007; 292(6):R2357-67. DOI: 10.1152/ajpregu.00687.2006. View

20.

Roforth M, Khosla S, Monroe D . Identification of Rorβ targets in cultured osteoblasts and in human bone. Biochem Biophys Res Commun. 2013; 440(4):768-73. PMC: 3856899. DOI: 10.1016/j.bbrc.2013.10.006. View