References
- Burris TP, Busby SA, Griffin PR. Targeting orphan nuclear receptors for treatment of metabolic diseases and autoimmunity. Chem Biol. 2012;19(1):51–59.
- Mullican SE, DiSpirito JR, Lazar MA. The orphan nuclear receptors at their 25-year reunion. J Mol Endocrinol. 2013;51:T115–T140.
- Jetten AM, Cook DN. (Inverse) agonists of retinoic acid–related orphan receptor γ: regulation of immune responses, inflammation, and autoimmune disease. Annu Rev Pharmacol Toxicol. 2020;60(1):371–390.
- Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126(6):1121–1133.
- Interleukin VM. 17 is a chief orchestrator of immunity. Nat Immunol. 2017;18(6):612–621.
- Balato A, Scala E, Balato N, et al. Biologics that inhibit the Th17 pathway and related cytokines to treat inflammatory disorders. Expert Opin Biol Ther. 2017;17(11):1363–1374.
- Hawkes JE, Chan TC, Krueger JG. Psoriasis pathogenesis and the development of novel targeted immune therapies. J Allergy Clin Immunol. 2017;140(3):645–653.
- Fauber BP, 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.
- Kumar N, Solt LA, Conkright JJ, et al. 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-α/γ Inverse Agonist. Mol Pharmacol. 2010;77(2):228–236.
- Solt LA, Kumar N, Nuhant P, et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature. 2011;472(7344):491–494.
- Zhang Y, Luo X, Wu D, et al. ROR nuclear receptors: structure, related diseases, and drug discovery. Acta Pharmacol Sin. 2015;36(1):71–87.
- Cyr P, Bronner SM, Crawford JJ. Recent progress on nuclear receptor RORγ modulators. Bioorg Med Chem Lett. 2016;26(18):4387–4393.
- Bronner SM, Zbieg JR, Crawford JJ. RORγ antagonists and inverse agonists: a patent review. Expert Opin Ther Pat. 2017;27(1):101–112.
- Panya VB, Kumar S, Sachchidanand S, et al. 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.
- Sun H, 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.
- Slominski AT, Kim TK, Hobrath JV, et al. Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols. Sci Rep. 2017;7(1):11434.
- Ladurner A, Schwarz PF, Dirsch VM. Natural products as modulators of retinoic acid receptor-related orphan receptors (RORs). Nat Prod Rep. 2021;38(4):757–781.
- Gege C. RORγt inhibitors as potential back-ups for the phase II candidate VTP-43742 from Vitae Pharmaceuticals: patent evaluation of WO2016061160 and US20160122345. Expert Opin Ther Pat. 2017;27(1):1–8.
- Gege C. Retinoid-related orphan receptor gamma t (RORγt) inhibitors from Vitae Pharmaceuticals (WO2015116904) and structure proposal for their Phase I candidate VTP-43742. Expert Opin Ther Pat. 2016;26(6):737–744.
- Narjes F. The discovery of AZD0284, an inverse agonist of the nuclear receptor RORγ. Drug Design and Delivery Symposium, Oct 26, 2017; American Chemical Society: Washington DC. [cited 2017 Oct 26]. Available from: www.acs.org/content/acs/en/acs-webinars/drug-discovery/psoriasis.html
- Kallen J, Izaac A, Be C, et al. Structural states of RORγt: x-ray elucidation of molecular mechanisms and binding interactions for natural and synthetic compounds. ChemMedChem. 2017;12(13):1014–1021.
- Vitae Pharmaceuticals, 8-K - Current report, published: 2016-Mar-16. [cited 2021 Mar 15]. Available from: https://sec.report/Document/0001104659-16-105501/
- Whitehead GS, Kang HS, Thomas SY, et al. Therapeutic suppression of pulmonary neutrophilia and allergic airway hyperresponsiveness by an RORγt inverse agonist. JCI Insight. 2019;4(14):e125528.
- Smith SH, Peredo CE, Takeda Y, et al. Development of a topical treatment for psoriasis targeting RORγ: from bench to skin. PLoS ONE. 2016;11(2):e0147979.
- Kang EG, Wu S, Gupta A, et al. A Phase I randomised controlled trial to evaluate safety and clinical effect of topically applied GSK2981278 ointment in a psoriasis plaque test. Br J Dermatol. 2018;178(6):1427–1429.
- Wang Y, Cai W, Zhang G, et al. 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.
- Gege C, Schlüter 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):5265–5267.
- Wang Y, Cai W, Cheng Y, et al. Discovery of biaryl amides as potent, orally bioavailable, and CNS penetrant RORγt inhibitors. ACS Med Chem Lett. 2015;6(7):787–792.
- Guntermann C, Piaia A, Hamel ML, et al. Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations. JCI Insight. 2017;2(5):e91127.
- Skepner J, Ramesh R, Trocha M, et al. Pharmacologic inhibition of RORγt regulates Th17 signature gene expression and suppresses cutaneous inflammation in vivo. J Immunol. 2014;192(6):2564–2575.
- Exelixis 2010 Annual Report, [cited 2021 May 2]. Available from: https://ir.exelixis.com/annual-reports
- Arrowsmith CH, Audia JE, Austin C, et al. The promise and peril of chemical probes. Nat Chem Biol. 2015;11(8):536–541.
- Gong H, Weinstein DS, Lu Z, et al. Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity. Bioorg Med Chem Lett. 2018;28(2):85–93.
- Steeneck C, Gege C, Kinzel O, et al. Discovery and optimization of new oxadiazole substituted thiazole RORγt inverse agonists through a bioisosteric amide replacement approach. Bioorg Med Chem Lett. 2020;30(12):127174.
- Gege C, Albers M, Kinzel O, et al. Optimization and biological evaluation of thiazole-bis-amide inverse agonists of RORγt. Bioorg Med Chem Lett. 2020;30(12):127205.
- Duan JJ-W, Lu Z, Jiang B, et al. Structure-based discovery of Phenyl (3-Phenylpyrrolidin-3-yl)sulfones as selective, orally active RORγt Inverse Agonists. ACS Med Chem Lett. 2019;10(3):367–373.
- Duan JJ, Jiang B, Lu Z, et al. Discovery of 2,6-difluorobenzyl ether series of phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfones as surprisingly potent, selective and orally bioavailable RORγt inverse agonists. Bioorg Med Chem Lett. 2020;30(19):127441.
- Marcoux D, Duan JJ, Shi Q, et al. Rationally designed, conformationally constrained inverse agonists of RORγt – identification of a potent, selective series with biologic-like in vivo efficacy. J Med Chem. 2019;62(21):9931–9946.
- Lu Z, Duan JJ, Xiao H, et al. Identification of potent, selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as RORγt inverse agonists. Bioorg Med Chem Lett. 2019;29(16):2265–2269.
- Cherney RJ, Cornelius LAM, Srivastava A, et al. Discovery of BMS-986251: a clinically viable, potent, and selective RORγt inverse agonist. ACS Med Chem Lett. 2020;11(6):1221–1227.
- Marcoux D, Bertrand MB, Weigelt CA, et al. Annulation reaction enables the identification of an exocyclic amide tricyclic chemotype as retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse agonists. Bioorg Med Chem Lett. 2020;30(19):127466.
- Shi Q, Xiao Z, Yang MG, et al. Tricyclic sulfones as potent, selective and efficacious RORγt inverse agonists - Exploring C6 and C8 SAR using late-stage functionalization. Bioorg Med Chem Lett. 2020;30(23):127521.
- Liu Q, Batt DG, Weigelt CA, et al. Novel tricyclic pyroglutamide derivatives as potent RORγt inverse agonists identified using a virtual screening approach. ACS Med Chem Lett. 2020;11(12):2510–2518.
- Harikrishnan LS, Gill P, Kamau MG, et al. Substituted benzyloxytricyclic compounds as retinoic acid-related orphan receptor gamma t (RORγt) agonists. Bioorg Med Chem Lett. 2020;30(12):127204.
- Jiang B, Duan JJ, Stachura S, et al. Discovery of (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidines as novel RORγt inverse agonists. Bioorg Med Chem Lett. 2020;30(17):127392.
- Haggerty HG, Sathish J, Gleason C, et al. Thymic lymphomas in a 6-month CByB6F1/Tg rasH2 carcinogenicity study with a RORγt inverse agonist, BMS-986251. Society of Toxicology (SOT) 59th Annual Meeting and Tox Expo 2020, Anaheim, California, USA. Poster #1121. [cited 2021 Feb 2]. Available from: www.criver.com/59th-annual-society-toxicology-meeting-and-toxexpo
- Burke JR, Cheng L, Gillooly KM, et al. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain. Sci Transl Med. 2019;11(502):eaaw1736.
- Yang MG, Beaudoin-Bertrand M, Xiao Z, et al. Tricyclic-carbocyclic RORγt inverse agonists - discovery of BMS-986313. J Med Chem. 2021;64(5):2714–2724.
- Development of antagonists to ROR-gamma. [cited 2021 May 2]. Available from: www.orphagen.com/autoimmune-disease/
- Harcken C, Csengery J, Turner M, et al. Discovery of a series of pyrazinone RORγ antagonists and identification of the clinical candidate BI 730357. ACS Med Chem Lett. 2021;12(1):143–154.
- Hirata K, Kotoku M, Seki N, et al. SAR exploration guided by LE and Fsp 3: discovery of a selective and orally efficacious RORγ inhibitor. ACS Med Chem Lett. 2016;7(1):23–27.
- Noguchi M, Nomura A, Murase K, et al. Ternary complex of human RORc ligand-binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment. Genes Cells. 2017;22(6):535–551.
- Noguchi M, Nomura A, Doi S, et al. Ternary crystal structure of human RORγ ligand-binding-domain, an inhibitor and corepressor peptide provides a new insight into corepressor interaction. Sci Rep. 2018;8(1):17374.
- Kotoku M, Maeba T, Fujioka S, et al. Discovery of second generation RORγ inhibitors composed of an azole scaffold. J Med Chem. 2019;62(5):2837–2842.
- Pharmaceutical business clinical development as of February 9, 2021. [cited 2021 May 2]. Available from: jt.com/investors/results/presentation_financial/index.html.
- Akos Pharmaceuticals pipeline. [cited 2021 May 2]. Available from: www.akrospharma.com/pipeline-products/pipe/
- Fukase Y, Sato A, Tomata Y, et al. Identification of novel quinazolinedione derivatives as RORγt inverse agonist. Bioorg Med Chem. 2018;26(3):721–736.
- Sato A, Fukase Y, Kono M, et al. Design and synthesis of conformationally constrained RORγt inverse agonists. ChemMedChem. 2019;14(22):1917–1932.
- Shirai J, Tomata Y, Kono M, et al. Discovery of orally efficacious RORγt inverse agonists, part 1: identification of novel phenylglycinamides as lead scaffolds. Bioorg Med Chem. 2018;26(2):483–500.
- Kono M, Oda T, Tawada M, et al. Discovery of orally efficacious RORγt inverse agonists. part 2: design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives. Bioorg Med Chem. 2018;26(2):470–482.
- Kono M, Ochida A, Oda T, et al. Discovery of [cis-3-({(5R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl}carbonyl)cyclobutyl]acetic acid (TAK-828F) as a potent, selective, and orally available novel retinoic acid receptor-related orphan receptor γt inverse agonist. J Med Chem. 2018;61(7):2973–2988.
- Nakamura Y, Igaki K, Uga K, et al. Pharmacological evaluation of TAK-828F, a novel orally available RORγt inverse agonist, on murine chronic experimental autoimmune encephalomyelitis model. J Neuroimmunol. 2019;335:577016.
- Shibata A, Uga K, Sato T, et al. Pharmacological inhibitory profile of TAK-828F, a potent and selective orally available RORγt inverse agonist. Biochem Pharmacol. 2018;150:35.
- Nakagawa H, Koyama R, Kamada Y, et al. Biochemical properties of TAK-828F, a potent and selective retinoid-related orphan receptor gamma t inverse agonist. Pharmacology. 2018;102(5–6):244–252.
- Igaki K, Nakamura Y, Komoike Y, et al. Pharmacological evaluation of TAK-828F, a novel orally available RORγt inverse agonist, on murine colitis model. Inflammation. 2019;42(1):91–102.
- Igaki K, Nakamura Y, Tanaka M, et al. Pharmacological effects of TAK-828F: an orally available RORγt inverse agonist, in mouse colitis model and human blood cells of inflammatory bowel disease. Inflamm Res. 2019;68(6):493–509.
- Takeda FY2016 Q4 results, databook, May 2017. [cited 2021 Feb 13]. Available from: www.takeda.com/investors/financial-results/2016/
- Yukawa T, Nara Y, Kono M, et al. Design, synthesis, and biological evaluation of retinoic acid-related orphan receptor γt (RORγt) agonist - structure-based functionality switching approach from in house RORγt inverse agonist to RORγt agonist. J Med Chem. 2019;62(3):1167–1179.
- Olsson RI, Xue Y, von Berg S, et al. Benzoxazepines achieve potent suppression of IL-17 release in human T-helper 17 (TH17) cells through an induced-fit binding mode to the nuclear receptor RORγ. ChemMedChem. 2016;11(2):207–216.
- Narjes F, Xue Y, von Berg S, et al. Structure-based design leads to potent and orally bioavailable inverse agonists of RORγt. J Med Chem. 2018;61(17):7796–7813.
- von Berg S, Xue Y, Collins M, et al. Discovery of potent and orally bioavailable inverse agonists of the retinoic acid receptor-related orphan receptor C2. ACS Med Chem Lett. 2019;10(6):972–977.
- Asimus S, Palmér R, Albayaty M, et al. Pharmacokinetics, pharmacodynamics and safety of the inverse retinoic acid‐related orphan receptor γ agonist AZD0284. Br J Clin Pharmacol. 2020;86(7):1398–1405.
- Schnute ME, Wennerstal M, Alley J, et al. Discovery of 3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide: a potent, selective, and orally bioavailable retinoic acid receptor-related orphan receptor C2 inverse agonist. J Med Chem. 2018;61(23):10415–10439.
- Wang Y, Liu H. A drug with lipophilicity-dependent potency can be metabolically stable: discovery of a potent and selective retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonist as an orally bioavailable anti-inflammatory agent. J Med Chem. 2018;61(23):10412–10414.
- The granted US patents US9920054, US10426135 claim solely these structure and also the prosecution of WO2016/046755 in Europe named this structure as preferred compound in intented claim 21 (now withdrawn).
- Berstein G, Zhang Y, Berger Z, et al. A phase I, randomized, double-blind study to assess the safety, tolerability and efficacy of the topical RORC2 inverse agonist PF-06763809 in participants with mild-to-moderate plaque psoriasis. Clin Exp Dermatol. 2021;46(1):122–129.
- Amaudrut J, Argiriadi MA, Barth M, et al. Discovery of novel quinoline sulphonamide derivatives as potent, selective and orally active RORgamma inverse agonists. Bioorg Med Chem Lett. 2019;29(14):1799–1806.
- Second patent application WO2016/198908 covers less, but the same compounds claiming only one priority application.
- Gauld SB, Jacquet S, Gauvin D, et al. Inhibition of Interleukin-23–Mediated inflammation with a novel small molecule inverse agonist of RORγt. J Pharmacol Exp Ther. 2019;371(1):208–218.
- Kannan AK, Su Z, Gauvin DM, et al. IL-23 induces regulatory T cell plasticity with implications for inflammatory skin diseases. Sci Rep. 2019;9(1):17675.
- ABBV-553: the depicted formula in Fig. 4B for ABBV-553 was one of four preferred structures in EP3307734B and application US2019/0055196 was the continuation of US10106501 (many structures granted) which has now been abandoned.
- AbbVie (ABBV) Q1 2021 earnings call transcript. [cited 2021 May 3]. Available from: www.fool.com/earnings/call-transcripts/2021/04/30/abbvie-abbv-q1-2021-earnings-call-transcript/
- Rose J, Carlson N, Yerramreddy V, et al. Discovery of ARN-6039 as a potent, orally available inverse agonist of RORγt for autoimmune neuroinflammatory demyelinating disease. Neurology. 2016;86(16 Supplement):99.
- Kumar N, Lyda B, Chang MR, et al. Identification of SR2211: a potent synthetic RORγ-selective modulator. ACS Chem Biol. 2012;7(4):672–677.
- Chang MR, Lyda B, Kamenecka TM, et al. Pharmacologic repression of retinoic acid receptor-related orphan nuclear receptor γ is therapeutic in the collagen-induced arthritis experimental model. Arthritis Rheum. 2014;66(3):579–588.
- Jiang X, Dulubova I, Reisman SA, et al. A novel series of cysteine-dependent, allosteric inverse agonists of the nuclear receptor RORγt. Bioorg Med Chem Lett. 2020;30(6):126967.
- Scheepstra M, Leysen S, van Almen GC, et al. Identification of an allosteric binding site for RORγt inhibition. Nat Commun. 2015;6(1):8833.
- Dulubova I, Jian X, Trevino I, et al. RTA 1701 is an orally-bioavailable, potent, and selective RORγt inhibitor that suppresses Th17 differentiation in vitro and is efficacious in mouse models of autoimmune disease. J Immunol. 2018;200(1 suppl):121.14.
- Reisman SA, Lee CY, Proksch JW, et al. RTA 1701 is an oral RORγt inhibitor that suppresses the IL-17A response in non-human primates. J Immunol. 2018;200(1 suppl):175.22.
- Tanis VM, Venkatesan H, Cummings MD, et al. 3-Substituted quinolines as RORγt inverse agonists. Bioorg Med Chem Lett. 2019;29(12):1463–1470.
- Xue X, Soroosh P, De Leon-Tabaldo A, et al. Pharmacologic modulation of RORγt translates to efficacy in preclinical and translational models of psoriasis and inflammatory arthritis. Sci Rep. 2016;6(1):37977.
- Kummer DA, Cummings MD, Abad M, et al. Identification and structure activity relationships of quinoline tertiary alcohol modulators of RORγt. Bioorg Med Chem Lett. 2017;27(9):2047–2057.
- Barbay JK, Cummings MD, Abad M, et al. 6-Substituted quinolines as RORγt inverse agonists. Bioorg Med Chem Lett. 2017;27(23):5277–5283.
- Gege C, Cummings MD, Albers M, et al. Identification and biological evaluation of thiazole-based inverse agonists of RORγt. Bioorg Med Chem Lett. 2018;28(9):1446–1455.
- Phenex AG announces milestone payment from Janssen for the entry of RORgt inhibitor into Phase I. [cited 2021 Feb 18]. Available from: www.phenex-pharma.com/phenex-ag-announces-milestone-payment-from-janssen-for-the-entry-of-rorgt-inhibitor-into-phase-i/
- Bassolas-Molina H, Raymond E, Labadia M, et al. An RORgt oral inhibitor modulates IL-17 responses in peripheral blood and intestinal mucosa of Crohn’s disease patients. Front Immunol. 2018;9:2307.
- Venken K, Jacques P, Mortier C, et al. RORγt inhibition selectively targets IL-17 producing iNKT and γδ-T cells enriched in Spondyloarthritis patients. Nat Commun. 2019;10(1):9.
- Tasler S. Small molecule inhibitors of IL-17A and IL-17F for the treatment of autoimmune diseases. Presentation at the 244th ACS National Meeting, Philadelphia, August 19th, 2012.
- Kohlhof H, Hietel B, Schenk M, et al. IMU-935: orally available small molecule inhibitor of IL-17 with unique molecular profile for the treatment of autoimmune diseases. CMMI 2019, Trondheim, Norway, 2019, June 3-6. [cited 2021 Jan 21]. Available from: www.immunic-therapeutics.com/imu935/
- Basarab GS, Hill PJ, Rastagar A, et al. Design of helicobacter pylori glutamate racemase inhibitors as selective antibacterial agents: a novel pro-drug approach to increase exposure. Bioorg Med Chem Lett. 2008;18(16):4716–4722.
- Guo Y, MacIsaac KD, Chen Y, et al. Inhibition of RORγt skews TCRα gene rearrangement and limits T cell repertoire diversity. Cell Rep. 2016;17(12):3206–3218.
- Zhang H, Lapointe BT, Anthony N, et al. Discovery of N-(Indazol-3-yl)piperidine-4-carboxylic acids as RORγt allosteric inhibitors for autoimmune diseases. ACS Med Chem Lett. 2020;11(2):114–119.
- Leijten-van de Gevel IA, Brunsveld L. Delineation of the molecular determinants of the unique allosteric binding site of the orphan nuclear receptor RORγt. J Biol Chem. 2020;295(27):9183–9191.
- De Wit J, Al-Mossawi MH, Hühn MH, et al. RORγt inhibitors suppress TH17 responses in inflammatory arthritis and inflammatory bowel disease. J Allergy Clin Immunol. 2016;137(3):960–963.
- Fauber BP, Gobbi A, Robarge K, et al. Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists. Bioorg Med Chem Lett. 2015;25(15):2907–2912.
- Gege C. Retinoid-related orphan receptor γ t modulators: comparison of Glenmark’s me-too patent application (WO2015008234) with the originator application from merck sharp and Dohme (WO2012106995). Expert Opin Ther Pat. 2015;25(10):1215–1221.
- Ouvry G, Bouix-Peter C, Ciesielski F, et al. Discovery of phenoxyindazoles and phenylthioindazoles as RORγ inverse agonists. Bioorg Med Chem Lett. 2016;26(23):5802–5808.
- De Vries RMJM, Meijer FA, Doveston RG, et al. Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt. Proc Natl Acad Sci USA. 2021;118(6):e2021287118.
- Meijer FA, Oerlemans GJM, Brunsveld L. Orthosteric and allosteric dual targeting of the nuclear receptor RORγt with a bitopic ligand. ACS Chem Biol. 2021;16(3):510–519.
- Meijer F, Doveston RG, de Vries R, et al. Ligand-based design of allosteric retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonists. J Med Chem. 2020;63(1):241–259.
- Lao C, Zhou X, Chen H, et al. 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives as inhibitors of full-length RORγt. Bioorg Chem. 2019;90:103077.
- Rapalli VK, Waghule T, Gorantla S, et al. Psoriasis: pathological mechanisms, current pharmacological therapies, and emerging drug delivery systems. Drug Discov Today. 2020;25(12):2212–2226.
- Huang M, Bolin S, Miller H, et al. RORγ structural plasticity and druggability. Int J Mol Sci. 2020;21(15):5329.
- Hornberg JJ, Laursen M, Brenden N, et al. Exploratory toxicology as an integrated part of drug discovery. Part I: why and how. Drug Discov Today. 2014;19:1131–1136.
- Hornberg JJ, Laursen M, Brenden N, et al. Exploratory toxicology as an integrated part of drug discovery. Part II: screening strategies. Drug Discov Today. 2014;19(8):1137–1144.
- Shen J, Swift B, Mamelok R, et al. Design and conduct considerations for first-in-human trials. Clin Transl Sci. 2018;12(1):6–19.
- Ouvry G, Atrux-Tallau N, Bihl F, et al. Discovery and characterization of CD12681, a potent RORγ inverse agonist, preclinical candidate for the topical treatment of psoriasis. ChemMedChem. 2018;13(4):321–337.
- [cited 2021 Feb 28]. Available from: http://www.glenmarkpharma.com/content/rd-pipeline
- Balogh EA, Bashyam AM, Ghamrawi RI, et al. Emerging systemic drugs in the treatment of plaque psoriasis. Expert Opin Emerg Drugs. 2020;25(2):89–100.
- Ghoreschi K, Balato A, Enerbäck C, et al. Therapeutics targeting the IL-23 and IL-17 pathway in psoriasis. Lancet. 2021;397(10275):754–766.
- Reich K, Papp KA, Blauvelt A, et al. Bimekizumab versus ustekinumab for the treatment of moderate to severe plaque psoriasis (BE VIVID): efficacy and safety from a 52-week, multicentre, double-blind, active comparator and placebo controlled phase 3 trial. Lancet. 2021;397(10273):487–498.
- Torres T, Puig L. Apremilast: a novel oral treatment for psoriasis and psoriatic arthritis. Am J Clin Dermatol. 2018;19(1):23–32.
- Beringer A, Noack M, Miossec P. IL-17 in chronic inflammation: from discovery to targeting. Trends Mol Med. 2016;22(3):230–241.
- Lai AV, Crews CM. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov. 2017;16(2):101–114.
- Sun Z, Unutmaz D, Zou Y, et al. Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science. 2000;288(5475):2369–2373.
- He Z, Ma J, Wang R, et al. A two-amino-acid substitution in the transcription factor RORγt disrupts its function in TH17 differentiation but not in thymocyte development. Nat Immunol. 2017;18(10):1128–1138.
- Wang Y, Yang T, Liu Q, et al. Discovery of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists. Bioorg Med Chem. 2015;23(17):5293–5302.
- Chianelli D, Rucker PV, Roland J, et al. Nidufexor (LMB763), a novel FXR modulator for the treatment of nonalcoholic steatohepatitis. J Med Chem. 2020;63(8):3868–3880.
- Dufour J, Caussy C, Loomba R. Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges. Gut. 2020;69(10):1877–1884.
- Wang J, Zou JX, Xue X, et al. ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. Nat Med. 2016;22(5):488–496.
- Wu X, Wang J, Liu K, et al. Are Th17 cells and their cytokines a therapeutic target in Guillain-Barré syndrome? Expert Opin Ther Targets. 2016;20(2):209–222.