Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ROR(GMMA)T Modulating Activity for the Treatment of Cancers Robert B. Kargbo* Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States predominantly highly expressed in the thymus, where it has been identified in immature CD4+/CD8+ thymocytes as well as lymphoid tissue inducer (LTi) cells. The ligand binding domains (LDBs) of RORγ1 and RORγt are identical, and the crystal structures of the LBD of RORγt with various ligands have been reported. A number of key RORγ modulators have been described in the peer-reviewed literature including hexafluoro-isopropanol derivatives as inverse agonist, sulfonamide derivatives as agonist or inverse agonist, and so forth. In another development, a class of carboxylic acid as inverse agonists of RORγ do not bind to the ligand binding pocket but to a previously unrecognized allosteric site. Nonetheless, the first human proof of concept was recently announced in a randomized doubleblind, placebo-controlled Phase IIa trial in patients with moderate to severe psoriasis (https://clinicaltrials.gov/ct2/ show/NCT02555709?cond=VTP-43742&rank=1, accessed 05/05/2018). In this patent disclosure, compounds in this invention have RORγt inhibitory action and are useful chemotherapeutic drugs for hyperproliferative disorders, malignant tumor, ovarian cancer, breast cancer, Hodgkin’s disease, inflammatory diseases, rheumatoid arthritis, and so forth. Definitions. A is a substituted ring; L1 is a bond, halogenated C1−2 alkylene, −NH− or −O−; R1 and R2 are independently a hydrogen atom or a substituent; R3 is a substituent; ring D is a further substituted ring; L2 is −SO2−, −S(O)− or −S(O)(NR4)−;
Important Compound Classes.
Title. Heterocyclic Compounds with an ROR(GAMMA)T Modulating Activity Patent Application Number. WO 2018/030550 A1 Publication Date. February 15, 2018 Priority Application. US 62/372522 US 62/485170 Priority Date. August 09, 2016 April 13, 2017 Inventors. Yamamoto, S.; Shirai, J.; Kono, M.; Shiokawa, Z.; Yukawa, T.; Imada, T.; Negoro, N.; Oda, T.; Sasaki, S.; Nara, Y.; Suzuki, S.; Sato, A.; Ishii, N.; Shibuya, A.; Nakagawa, Y.; Cole, D.; Gibson, T.; Ivetac, A.; Swann, S.; Tyhonas, J. Assignee Company. Takeda Pharmaceutical Company Limited Disease Area. Cancer Biological Target. Retinoid-related Orphan Receptor (ROR)γt. Summary. Nuclear receptors (NR) are a super family of intracellular receptors involved in the regulation of many biological functions including organ physiology, cell differentiation, and embryonic development. There are 48 nuclear receptors that have been identified in humans, and some are recognized as important pathological regulators in disease processes such as autoimmune diseases, cancers, and diabetes. Many notable pharmaceutical agents like cortisone (antiinflammatory), progesterone (contraceptive), rosiglitazone (diabetes), and so forth, accounted for roughly 13% of all pharmaceutical sales in the United States in 2009. RAR-related orphan nuclear receptor gamma (RORγ) has seen a renewed interest as potential treatment for a variety of disorders like rheumatoid arthritis, autoimmune disorders, multiple sclerosis, psoriasis, psoriatic arthritis, and so forth. The pathology of the immune diseases has shown the involvement of T cells, T helper 17 cells (Th17 cell), inter alia, and inflammatory cytokines such as IL-17A and IL-17F. Antibodies against IL-17 and IL-23 have validated the IL-23 and IL-17 pathway in humans. Several clinical candidates have also been identified, and proofs of concept have demonstrated that antibodies inhibiting the activity of IL-17 family can be used for the treatment of the aforementioned diseases. RORγ exists in two isoforms. RORγ (also referred to as RORγ1) is expressed in the lung, liver, kidney, muscle, brown fat, and thymus. Furthermore, even though RORγ1 is abundantly expressed, detecting the protein has been challenging. However, RORγt is © XXXX American Chemical Society
X is a carbon atom or a nitrogen atom; n is an integer of 1 or 2; ring B is a further substituted 6- or 7-membered oxygencontaining heterocycle; Y1, Y2, and Y3 are independently a carbon atom or a nitrogen atom; ring C is a further substituted 6-membered aromatic ring, and Y4 is CH− or N− or a salt thereof. Received: May 10, 2018
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DOI: 10.1021/acsmedchemlett.8b00216 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
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Key Structures.
Patent Highlight
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Robert B. Kargbo: 0000-0002-5539-6343 Notes
The author declares no competing financial interest.
Biological Assay. The biological activity of compounds in this invention were tested for RORγ activity by a time-resolved fluorescence resonance energy transfer method (TR-FRET) utilizing histidine-tagged RORγt, fluorescent-labeled synthetic ligand, and terbium-labeled antihistamine tag antibody. In another assay, Jurkat reporter test, a human ROR response element was inserted into the upstream of luciferase of pGL 4.28 reporter vector, and RORyt sequence was inserted into the downstream of cytomegalovirus (CMV) promoter. In addition, mouse Th17 ̈ T cells colcell differentiation test used CD4 positive naive lected from spleen cells of mice. Test compounds were evaluated on their ability to modulate IL-17A production in cells derived from the mouse spleen at 3 μM. Biological Data. The Table below shows results of the activity of test compound to modulate IL-17A production in cells derived from mouse spleen (% of control of a test compound at 3 μM).
Recent Review Articles. 1. Fauber, B. P.; Magnuson, S. J. Med. Chem. 2014, 57, 5871−5892. 2. Zhong, C.; Zhu, J. Trends Immunol. 2017, 38, 229−231. 3. Liljevald, M.; Rehnberg, M.; Söderberg, M.; Ramnegård, M.; Börjesson, J.; Luciani, D.; Krutrök, N.; Brändén, L.; Johanssen, C.; Xu, X.; Bjursell, M.; Sjögren, A.-K.; Hornberg, J.; Andersson, U.; Keeling, D.; Jirholt, J. Autoimmun. Rev. 2016, 15, 1062−1070. 4. Rutz, S.; Eidenschenk, C.; Kiefer, J. R.; Ouyang, W. Cytokine Growth Factor Rev. 2016, 30, 1−17. B
DOI: 10.1021/acsmedchemlett.8b00216 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
