Identification of Imidazo[1,2-]pyridazine Derivatives As Potent, Selective, and Orally Active Tyk2 JH2 Inhibitors

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Mar 21

PMID 30891145

Citations 9

Authors

Chunjian Liu

James Lin

Ryan Moslin

John S Tokarski

Jodi Muckelbauer

Chiehying Chang

Jeffrey Tredup

Dianlin Xie

Hyunsoo Park

Peng Li

Dauh-Rurng Wu

Joann Strnad

Adriana Zupa-Fernandez

Lihong Cheng

Charu Chaudhry

Jing Chen

Cliff Chen

Huadong Sun

Paul Elzinga

Celia DArienzo

Kathleen Gillooly

Tracy L Taylor

Kim W McIntyre

Luisa Salter-Cid

Louis J Lombardo

Percy H Carter

Nelly Aranibar

James R Burke

David S Weinstein

Affiliations

Soon will be listed here.

Abstract

In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor , which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

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References

Bengtsson A, Sturfelt G, Truedsson L, Blomberg J, Alm G, Vallin H . Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies. Lupus. 2001; 9(9):664-71. DOI: 10.1191/096120300674499064. View

ORTMANN R, Smeltz R, Yap G, Sher A, Shevach E . A heritable defect in IL-12 signaling in B10.Q/J mice. I. In vitro analysis. J Immunol. 2001; 166(9):5712-9. DOI: 10.4049/jimmunol.166.9.5712. View

Shuai K, Liu B . Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol. 2003; 3(11):900-11. DOI: 10.1038/nri1226. View

Lee E, Trepicchio W, Oestreicher J, Pittman D, Wang F, Chamian F . Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004; 199(1):125-30. PMC: 1887731. DOI: 10.1084/jem.20030451. View

Piskin G, Tursen U, Sylva-Steenland R, Bos J, Teunissen M . Clinical improvement in chronic plaque-type psoriasis lesions after narrow-band UVB therapy is accompanied by a decrease in the expression of IFN-gamma inducers -- IL-12, IL-18 and IL-23. Exp Dermatol. 2004; 13(12):764-72. DOI: 10.1111/j.0906-6705.2004.00246.x. View

Nassar A, Kamel A, Clarimont C . Improving the decision-making process in the structural modification of drug candidates: enhancing metabolic stability. Drug Discov Today. 2004; 9(23):1020-8. DOI: 10.1016/S1359-6446(04)03280-5. View

Dallera M, Cardarelli P, Preston B, Witte A, Davis Jr J . Type I interferon correlates with serological and clinical manifestations of SLE. Ann Rheum Dis. 2005; 64(12):1692-7. PMC: 1755300. DOI: 10.1136/ard.2004.033753. View

Staerk J, Kallin A, Demoulin J, Vainchenker W, Constantinescu S . JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation: cross-talk with IGF1 receptor. J Biol Chem. 2005; 280(51):41893-9. DOI: 10.1074/jbc.C500358200. View

Piskin G, Sylva-Steenland R, Bos J, Teunissen M . In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol. 2006; 176(3):1908-15. DOI: 10.4049/jimmunol.176.3.1908. View

10.

Tada Y, Asahina A, Takekoshi T, Kishimoto E, Mitsui H, Saeki H . Interleukin 12 production by monocytes from patients with psoriasis and its inhibition by ciclosporin A. Br J Dermatol. 2006; 154(6):1180-3. DOI: 10.1111/j.1365-2133.2006.07180.x. View

11.

Papp K, Langley R, Lebwohl M, Krueger G, Szapary P, Yeilding N . Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008; 371(9625):1675-84. DOI: 10.1016/S0140-6736(08)60726-6. View

12.

Sandborn W, Feagan B, Fedorak R, Scherl E, Fleisher M, Katz S . A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology. 2008; 135(4):1130-41. DOI: 10.1053/j.gastro.2008.07.014. View

13.

Ghoreschi K, Laurence A, OShea J . Janus kinases in immune cell signaling. Immunol Rev. 2009; 228(1):273-87. PMC: 2782696. DOI: 10.1111/j.1600-065X.2008.00754.x. View

14.

Oyamada A, Ikebe H, Itsumi M, Saiwai H, Okada S, Shimoda K . Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis. J Immunol. 2009; 183(11):7539-46. DOI: 10.4049/jimmunol.0902740. View

15.

Kimball A, Gordon K, Fakharzadeh S, Yeilding N, Szapary P, Schenkel B . Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years. Br J Dermatol. 2012; 166(4):861-72. DOI: 10.1111/j.1365-2133.2012.10901.x. View

16.

Sandborn W, Gasink C, Gao L, Blank M, Johanns J, Guzzo C . Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N Engl J Med. 2012; 367(16):1519-28. DOI: 10.1056/NEJMoa1203572. View

17.

Liang J, Van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair W . Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors. J Med Chem. 2013; 56(11):4521-36. DOI: 10.1021/jm400266t. View

18.

Sohn S, Barrett K, Van Abbema A, Chang C, Kohli P, Kanda H . A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors. J Immunol. 2013; 191(5):2205-16. PMC: 3748334. DOI: 10.4049/jimmunol.1202859. View

19.

Kim T, Kanayama Y, Negoro N, Okamura M, Takeda T, Inoue T . Serum levels of interferons in patients with systemic lupus erythematosus. Clin Exp Immunol. 1987; 70(3):562-9. PMC: 1542177. View

20.

Liang Y, Zhu Y, Xia Y, Peng H, Yang X, Liu Y . Therapeutic potential of tyrosine kinase 2 in autoimmunity. Expert Opin Ther Targets. 2014; 18(5):571-80. DOI: 10.1517/14728222.2014.892925. View