Current Medicinal Chemistry

Author(s): Surya K. De*

DOI: 10.2174/0929867330666230216123419

Abrocitinib: First Globally Approved Selective Janus Kinase-1 Inhibitor for the Treatment of Atopic Dermatitis

Page: [4278 - 4282] Pages: 5

  • * (Excluding Mailing and Handling)

Abstract

Atopic dermatitis is epidermal hyperplasia, skin barrier dysfunction, and the aberrant activation of immune cells. Janus kinase (JAK) is a family of cytoplasmic nonreceptor tyrosine kinases that consists of four members, such as JAK1, JAK2, JAK3, and TYK2. The JAK signaling pathway plays a critical role in a wide range of autoimmune and inflammatory diseases, including atopic dermatitis. Abrocitinib is an orally bioavailable and selective JAK1 inhibitor, and it was approved in January, 2022, for the treatment of atopic dermatitis. The chemical structure and physical properties of abrocitinib, its synthesis, mechanism of action, and pharmacokinetic profile are summarized.

[1]
Mastraftsi, S.; Vrioni, G.; Bakakis, M.; Nicolaidou, E.; Rigopoulos, D.; Stratigos, A.J.; Gregoriou, S. Atopic dermatitis: Striving for reliable biomarkers. J. Clin. Med., 2022, 11(16), 4639.
[http://dx.doi.org/10.3390/jcm11164639] [PMID: 36012878]
[2]
Ständer, S. Atopic dermatitis. N. Engl. J. Med., 2021, 384(12), 1136-1143.
[http://dx.doi.org/10.1056/NEJMra2023911] [PMID: 33761208]
[3]
Ayen-Rodríguez, A.; Pereyra-Rodríguez, J.J.; Navarro-Triviño, F.J.; Alcantara-Luna, S.; Domínguez-Cruz, J.; Galán-Gutiérrez, M.; Vilar-Palomo, S.; Armario-Hita, J.C.; Ruiz-Villaverde, R. Long-term effectiveness and safety of biologic and small molecule drugs for moderate to severe atopic dermatitis: A systematic review. Life, 2022, 12(8), 1159.
[http://dx.doi.org/10.3390/life12081159] [PMID: 36013338]
[4]
Reich, K.; Thyssen, J.P.; Blauvelt, A.; Eyerich, K.; Soong, W.; Rice, Z.P.; Hong, H.C.; Katoh, N.; Valenzuela, F.; DiBonaventura, M.; Bratt, T.A.; Zhang, F.; Clibborn, C.; Rojo, R.; Valdez, H.; Kerkmann, U. Efficacy and safety of abrocitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis: A randomised, double-blind, multicentre phase 3 trial. Lancet, 2022, 400(10348), 273-282.
[http://dx.doi.org/10.1016/S0140-6736(22)01199-0] [PMID: 35871814]
[5]
Gooderham, M.J.; Forman, S.B.; Bissonnette, R.; Beebe, J.S.; Zhang, W.; Banfield, C.; Zhu, L.; Papacharalambous, J.; Vincent, M.S.; Peeva, E. Efficacy and safety of oral janus kinase 1 inhibitor abrocitinib for patients with atopic dermatitis. JAMA Dermatol., 2019, 155(12), 1371-1379.
[http://dx.doi.org/10.1001/jamadermatol.2019.2855] [PMID: 31577341]
[6]
Silverberg, J.I.; Simpson, E.L.; Thyssen, J.P.; Gooderham, M.; Chan, G.; Feeney, C.; Biswas, P.; Valdez, H.; DiBonaventura, M.; Nduaka, C.; Rojo, R. Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis. JAMA Dermatol., 2020, 156(8), 863-873.
[http://dx.doi.org/10.1001/jamadermatol.2020.1406] [PMID: 32492087]
[7]
Le, M.; Berman-Rosa, M.; Ghazawi, F.M.; Bourcier, M.; Fiorillo, L.; Gooderham, M.; Guenther, L.; Hanna, S.; Hong, H.C.H.; Landells, I.; Lansang, P.; Marcoux, D.; Wiseman, M.C.; Yeung, J.; Lynde, C.; Litvinov, I.V. Systematic review on the efficacy and safety of oral janus kinase inhibitors for the treatment of atopic dermatitis. Front. Med., 2021, 8, 682547.
[http://dx.doi.org/10.3389/fmed.2021.682547] [PMID: 34540860]
[8]
Bieber, T.; Simpson, E.L.; Silverberg, J.I.; Thaçi, D.; Paul, C.; Pink, A.E.; Kataoka, Y.; Chu, C.Y.; DiBonaventura, M.; Rojo, R.; Antinew, J.; Ionita, I.; Sinclair, R.; Forman, S.; Zdybski, J.; Biswas, P.; Malhotra, B.; Zhang, F.; Valdez, H. Abrocitinib versus placebo or dupilumab for atopic dermatitis. N. Engl. J. Med., 2021, 384(12), 1101-1112.
[http://dx.doi.org/10.1056/NEJMoa2019380] [PMID: 33761207]
[9]
Crowley, E.L.; Nezamololama, N.; Papp, K.; Gooderham, M.J. Abrocitinib for the treatment of atopic dermatitis. Expert Rev. Clin. Immunol., 2020, 16(10), 955-962.
[http://dx.doi.org/10.1080/1744666X.2021.1828068] [PMID: 32969750]
[10]
Simpson, E.L.; Sinclair, R.; Forman, S.; Wollenberg, A.; Aschoff, R.; Cork, M.; Bieber, T.; Thyssen, J.P.; Yosipovitch, G.; Flohr, C.; Magnolo, N.; Maari, C.; Feeney, C.; Biswas, P.; Tatulych, S.; Valdez, H.; Rojo, R. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): A multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet, 2020, 396(10246), 255-266.
[http://dx.doi.org/10.1016/S0140-6736(20)30732-7] [PMID: 32711801]
[11]
Vazquez, M.L.; Kaila, N.; Strohbach, J.W.; Trzupek, J.D.; Brown, M.F.; Flanagan, M.E.; Mitton-Fry, M.J.; Johnson, T.A.; TenBrink, R.E.; Arnold, E.P.; Basak, A.; Heasley, S.E.; Kwon, S.; Langille, J.; Parikh, M.D.; Griffin, S.H.; Casavant, J.M.; Duclos, B.A.; Fenwick, A.E.; Harris, T.M.; Han, S.; Caspers, N.; Dowty, M.E.; Yang, X.; Banker, M.E.; Hegen, M.; Symanowicz, P.T.; Li, L.; Wang, L.; Lin, T.H.; Jussif, J.; Clark, J.D.; Telliez, J.B.; Robinson, R.P.; Unwalla, R. Identification of N-cis -3-[Methyl(7 H -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutylpropane-1-sulfonamide (PF-04965842): A selective JAK1 clinical candidate for the treatment of autoimmune diseases. J. Med. Chem., 2018, 61(3), 1130-1152.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01598] [PMID: 29298069]
[12]
Connor, C.G.; DeForest, J.C.; Dietrich, P.; Do, N.M.; Doyle, K.M.; Eisenbeis, S.; Greenberg, E.; Griffin, S.H.; Jones, B.P.; Jones, K.N.; Karmilowicz, M.; Kumar, R.; Lewis, C.A.; McInturff, E.L.; McWilliams, J.C.; Mehta, R.; Nguyen, B.D.; Rane, A.M.; Samas, B.; Sitter, B.J.; Ward, H.W.; Webster, M.E. Development of a nitrene-type rearrangement for the commercial route of the JAK1 inhibitor abrocitinib. Org. Process Res. Dev., 2021, 25(3), 608-615.
[http://dx.doi.org/10.1021/acs.oprd.0c00366]
[13]
Bauman, J.N.; Doran, A.C.; King-Ahmad, A.; Sharma, R.; Walker, G.S.; Lin, J.; Lin, T.H.; Telliez, J.B.; Tripathy, S.; Goosen, T.C.; Banfield, C.; Malhotra, B.K.; Dowty, M.E. The pharmacokinetics, metabolism, and clearance mechanisms of abrocitinib, a selective janus kinase inhibitor, in humans. Drug Metab. Dispos., 2022, 50(8), 1106-1118.
[http://dx.doi.org/10.1124/dmd.122.000829] [PMID: 35701182]
[14]
Ortiz de M.P.R.. Hydrocarbon hydroxylation by cytochrome P450 enzymes. Chem. Rev., 2010, 110(2), 932-948.
[http://dx.doi.org/10.1021/cr9002193] [PMID: 19769330]
[15]
Nogueira, M.; Torres, T. Janus kinase inhibitors for the treatment of atopic dermatitis: Focus on abrocitinib, baricitinib, and upadacitinib. Dermatol. Pract. Concept., 2021, 11(4), e2021145.
[http://dx.doi.org/10.5826/dpc.1104a145] [PMID: 35024237]
[16]
He, H.; Guttman-Yassky, E. JAK inhibitors for atopic dermatitis: An update. Am. J. Clin. Dermatol., 2019, 20(2), 181-192.
[http://dx.doi.org/10.1007/s40257-018-0413-2] [PMID: 30536048]
[17]
Peeva, E.; Hodge, M.R.; Kieras, E.; Vazquez, M.L.; Goteti, K.; Tarabar, S.G.; Alvey, C.W.; Banfield, C. Evaluation of a janus kinase 1 inhibitor, PF-04965842, in healthy subjects: A phase 1, randomized, placebo-controlled, dose-escalation study. Br. J. Clin. Pharmacol., 2018, 84(8), 1776-1788.
[http://dx.doi.org/10.1111/bcp.13612] [PMID: 29672897]
[18]
Lee, K.P.; Plante, J.; Korte, J.E.; Elston, D.M. Oral Janus kinase inhibitors in the treatment of atopic dermatitis: A systematic review and meta‐analysis. Skin Health Dis., 2022, 2022, e133.
[http://dx.doi.org/10.1002/ski2.133]
[19]
Cartron, A.M.; Nguyen, T.H.; Roh, Y.S.; Kwatra, M.M.; Kwatra, S.G. Janus kinase inhibitors for atopic dermatitis: A promising treatment modality. Clin. Exp. Dermatol., 2021, 46(5), 820-824.
[http://dx.doi.org/10.1111/ced.14567] [PMID: 33484582]