Discovery of Orally Available Prodrugs of Itaconate and Derivatives
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články
Grantová podpora
R01 AR068280
NIAMS NIH HHS - United States
R01 AR074846
NIAMS NIH HHS - United States
PubMed
39848624
PubMed Central
PMC11995693
DOI
10.1021/acs.jmedchem.4c02646
Knihovny.cz E-zdroje
- MeSH
- aplikace orální MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- myši MeSH
- objevování léků MeSH
- prekurzory léčiv * chemie farmakologie chemická syntéza farmakokinetika MeSH
- sukcináty * chemie farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- itaconic acid MeSH Prohlížeč
- prekurzory léčiv * MeSH
- sukcináty * MeSH
Itaconate, an endogenous immunomodulator from the tricarboxylic acid (TCA) cycle, shows therapeutic effects in various disease models, but is highly polar with poor cellular permeability. We previously reported a novel, topical itaconate derivative, SCD-153, for the treatment of alopecia areata. Here, we present the discovery of orally available itaconate derivatives for systemic and skin disorders. Four sets of prodrugs were synthesized using pivaloyloxymethyl (POM), isopropyloxycarbonyloxymethyl (POC), (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL), and 3-(hexadecyloxy)propyl (HDP) pro-moieties pairing with itaconic acid (IA), 1-methyl itaconate (1-MI), and 4-methyl itaconate (4-MI). Among these, POC-based prodrugs (P2, P9, P13) showed favorable stability, permeability, and pharmacokinetics. Notably, P2 and P13 significantly inhibited Poly(I:C)/IFNγ-induced inflammatory cytokines in human epidermal keratinocytes. Oral studies demonstrated favorable pharmacokinetics releasing micromolar concentrations of IA or 4-MI from P2 and P13, respectively. These findings highlight the potential of prodrug strategies to enhance itaconate's cellular permeability and oral bioavailability, paving the way for clinical translation.
Zobrazit více v PubMed
O’Neill LAJ; Artyomov MN Itaconate: the poster child of metabolic reprogramming in macrophage function. Nat. Rev. Immunol 2019, 19 (5), 273–281. PubMed
Ferreira AV; Netea MG; Dominguez-Andres J. Itaconate as an immune modulator. Aging 2019, 11 (12), 3898–3899. PubMed PMC
Lampropoulou V; Sergushichev A; Bambouskova M; Nair S; Vincent EE; Loginicheva E; Cervantes-Barragan L; Ma X; Huang SC; Griss T; et al. Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation. Cell Metab. 2016, 24 (1), 158–166. PubMed PMC
Lawrence GW; Ovsepian SV; Wang J; Aoki KR; Dolly JO Extravesicular intraneuronal migration of internalized botulinum neurotoxins without detectable inhibition of distal neurotransmission. Biochem. J 2012, 441 (1), 443−452. PubMed
Qin W; Qin K; Zhang Y; Jia W; Chen Y; Cheng B; Peng L; Chen N; Liu Y; Zhou W; et al. S-glycosylation-based cysteine profiling reveals regulation of glycolysis by itaconate. Nat. Chem. Biol 2019, 15 (10), 983–991. PubMed
Song H; Xu T; Feng X; Lai Y; Yang Y; Zheng H; He X; Wei G; Liao W; Liao Y; et al. Itaconate prevents abdominal aortic aneurysm formation through inhibiting inflammation via activation of Nrf2. EBioMedicine 2020, 57, No. 102832. PubMed PMC
Bambouskova M; Gorvel L; Lampropoulou V; Sergushichev A; Loginicheva E; Johnson K; Korenfeld D; Mathyer ME; Kim H; Huang LH; et al. Electrophilic properties of itaconate and derivatives regulate the IkappaBzeta-ATF3 inflammatory axis. Nature 2018, 556 (7702), 501–504. PubMed PMC
Swain A; Bambouskova M; Kim H; Andhey PS; Duncan D; Auclair K; Chubukov V; Simons DM; Roddy TP; Stewart KM; Artyomov MN Comparative evaluation of itaconate and its derivatives reveals divergent inflammasome and type I interferon regulation in macrophages. Nat. Metab 2020, 2 (7), 594–602. PubMed PMC
Hooftman A; Angiari S; Hester S; Corcoran SE; Runtsch MC; Ling C; Ruzek MC; Slivka PF; McGettrick AF; Banahan K; et al. The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation. Cell Metab. 2020, 32 (3), 468–478.e7. PubMed PMC
Runtsch MC; Angiari S; Hooftman A; Wadhwa R; Zhang Y; Zheng Y; Spina JS; Ruzek MC; Argiriadi MA; McGettrick AF; et al. Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages. Cell Metab. 2022, 34 (3), 487–501.e8. PubMed
Yang S; Zhang X; Zhang H; Lin X; Chen X; Zhang Y; Lin X; Huang L; Zhuge Q. Dimethyl itaconate inhibits LPS-induced microglia inflammation and inflammasome-mediated pyroptosis via inducing autophagy and regulating the Nrf-2/HO-1 signaling pathway. Mol. Med. Rep 2021, 24 (3), No. 672, DOI: 10.3892/mmr.2021.12311. PubMed DOI PMC
Li W; Li Y; Kang J; Jiang H; Gong W; Chen L; Wu C; Liu M; Wu X; Zhao Y; Ren J. 4-octyl itaconate as a metabolite derivative inhibits inflammation via alkylation of STING. Cell Rep. 2023, 42 (3), No. 112145. PubMed
ElAzzouny M; Tom CT; Evans CR; Olson LL; Tanga MJ; Gallagher KA; Martin BR; Burant CF Dimethyl Itaconate Is Not Metabolized into Itaconate Intracellularly. J. Biol. Chem 2017, 292 (12), 4766–4769. PubMed PMC
Hooftman A; O’Neill LAJ The Immunomodulatory Potential of the Metabolite Itaconate. Trends Immunol. 2019, 40 (8), 687–698. PubMed
Lin J; Ren J; Gao DS; Dai Y; Yu L. The Emerging Application of Itaconate: Promising Molecular Targets and Therapeutic Opportunities. Front. Chem 2021, 9, No. 669308. PubMed PMC
Tsai J; Gori S; Alt J; Tiwari S; Iyer J; Talwar R; Hinsu D; Ahirwar K; Mohanty S; Khunt C; et al. Topical SCD-153, a 4-methyl itaconate prodrug, for the treatment of alopecia areata. PNAS Nexus 2023, 2 (1), No. pgac297. PubMed PMC
Hecker SJ; Erion MD Prodrugs of phosphates and phosphonates. J. Med. Chem 2008, 51 (8), 2328–2345. PubMed
Babu KS; Reddy MS; Tagore AR; Reddy GS; Sebastian S; Varma MS; Venkateswarlu G; Bhattacharya A; Reddy PP; Anand RV Efficient synthesis of olmesartan medoxomil, an antihypertensive drug. Synth. Commun 2008, 39 (2), 291–298.
Garaga S; Misra NC; Reddy AVR; Prabahar KJ; Takshinamoorthy C; Sanasi PD; Babu KR Commercial synthesis of Azilsartan Kamedoxomil: An angiotensin II receptor blocker. Org. Process Res. Dev 2015, 19 (4), 514–519.
Hostetler KY Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: current state of the art. Antiviral Res. 2009, 82 (2), A84–98. PubMed PMC
Pradere U; Garnier-Amblard EC; Coats SJ; Amblard F; Schinazi RF Synthesis of nucleoside phosphate and phosphonate prodrugs. Chem. Rev 2014, 114 (18), 9154–9218. PubMed PMC
Dash RP; Tichy T; Veeravalli V; Lam J; Alt J; Wu Y; Tenora L; Majer P; Slusher BS; Rais R. Enhanced Oral Bioavailability of 2-(Phosphonomethyl)-pentanedioic Acid (2-PMPA) from its (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL)-Based Prodrugs. Mol. Pharmaceutics 2019, 16 (10), 4292–4301. PubMed PMC
Majer P; Jancarik A; Krecmerova M; Tichy T; Tenora L; Wozniak K; Wu Y; Pommier E; Ferraris D; Rais R; Slusher BS Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedioic Acid (2-PMPA). J. Med. Chem 2016, 59 (6), 2810–2819. PubMed
Chollet AM; Le Diguarher T; Kucharczyk N; Loynel A; Bertrand M; Tucker G; Guilbaud N; Burbridge M; Pastoureau P; Fradin A; et al. Solid-phase synthesis of alpha-substituted 3-bisarylthio N-hydroxy propionamides as specific MMP inhibitors. Bioorg. Med. Chem 2002, 10 (3), 531–544. PubMed
Faller B. Artificial membrane assays to assess permeability. Curr. Drug Metab 2008, 9 (9), 886–892. PubMed
Daina A; Michielin O; Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep 2017, 7, No. 42717. PubMed PMC
Wils P; Warnery A; Phung-Ba V; Legrain S; Scherman D. High lipophilicity decreases drug transport across intestinal epithelial cells. J. Pharmacol. Exp. Ther 1994, 269 (2), 654–658. PubMed
Kawaguchi N; Ebihara T; Takeuchi T; Morohashi A; Yamasaki H; Tagawa Y; Takahashi J; Kondo T; Asahi S. Absorption of TAK-491, a new angiotensin II receptor antagonist, in animals. Xenobiotica 2013, 43 (2), 182–192. PubMed
Schurek KN; Wiebe R; Karlowsky JA; Rubinstein E; Hoban DJ; Zhanel GG Faropenem: review of a new oral penem. Expert Rev. Anti-Infect. Ther 2007, 5 (2), 185–198. PubMed
Tsaioun K; Blaauboer BJ; Hartung T. Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods. ALTEX 2016, 33 (4), 343–358. PubMed
Heidel KM; Dowd CS Phosphonate prodrugs: an overview and recent advances. Future Med. Chem 2019, 11 (13), 1625–1643. PubMed PMC
Shin JM; Choi DK; Sohn KC; Kim SY; Min Ha J; Ho Lee Y; Im M; Seo YJ; Deok Kim C; Lee JH; et al. Double-stranded RNA induces inflammation via the NF-kappaB pathway and inflammasome activation in the outer root sheath cells of hair follicles. Sci. Rep 2017, 7, No. 44127. PubMed PMC
Shin JM; Choi DK; Sohn KC; Koh JW; Lee YH; Seo YJ; Kim CD; Lee JH; Lee Y. Induction of alopecia areata in C3H/HeJ mice using polyinosinic-polycytidylic acid (poly[I:C]) and interferon-gamma. Sci. Rep 2018, 8 (1), No. 12518. PubMed PMC
Xing L; Dai Z; Jabbari A; Cerise JE; Higgins CA; Gong W; de Jong A; Harel S; DeStefano GM; Rothman L; et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat. Med 2014, 20 (9), 1043–1049. PubMed PMC
Pratt CH; King LE Jr.; Messenger AG; Christiano AM; Sundberg JP Alopecia areata. Nat. Rev. Dis Primers 2017, 3, No. 17011. PubMed PMC
Glickman JW; Dubin C; Renert-Yuval Y; Dahabreh D; Kimmel GW; Auyeung K; Estrada YD; Singer G; Krueger JG; Pavel AB; Guttman-Yassky E. Cross-sectional study of blood biomarkers of patients with moderate to severe alopecia areata reveals systemic immune and cardiovascular biomarker dysregulation. J. Am. Acad. Dermatol 2021, 84 (2), 370–380. PubMed
McPhee CG; Duncan FJ; Silva KA; King LE Jr.; Hogenesch H; Roopenian DC; Everts HB; Sundberg JP Increased expression of Cxcr3 and its ligands, Cxcl9 and Cxcl10, during the development of alopecia areata in the mouse. J. Invest. Dermatol 2012, 132 (6), 1736–1738. PubMed PMC
Hoffmann R. The potential role of cytokines and T cells in alopecia areata. J. Invest. Dermatol. Symp. Proc 1999, 4 (3), 235–238. PubMed
Hoffmann R; Eicheler W; Wenzel E; Happle R. Interleukin-1beta-induced inhibition of hair growth in vitro is mediated by cyclic AMP. J. Invest. Dermatol 1997, 108 (1), 40–42. PubMed
Hoffmann R; Eicheler W; Huth A; Wenzel E; Happle R. Cytokines and growth factors influence hair growth in vitro. Possible implications for the pathogenesis and treatment of alopecia areata. Arch. Dermatol. Res 1996, 288 (3), 153–156. PubMed
Hoffmann R; Wenzel E; Huth A; van der Steen P; Schaufele M; Henninger HP; Happle R. Cytokine mRNA levels in Alopecia areata before and after treatment with the contact allergen diphenylcyclopropenone. J. Invest. Dermatol 1994, 103 (4), 530–533. PubMed
Fetter T; de Graaf DM; Claus I; Wenzel J. Aberrant inflammasome activation as a driving force of human autoimmune skin disease. Front. Immunol 2023, 14, No. 1190388. PubMed PMC
Chen LL; Morcelle C; Cheng ZL; Chen X; Xu Y; Gao Y; Song J; Li Z; Smith MD; Shi M; et al. Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses. Nat. Cell Biol 2022, 24 (3), 353–363. PubMed PMC
Xie QM; Chen N; Song SM; Zhao CC; Ruan Y; Sha JF; Liu Q; Jiang XQ; Fei GH; Wu HM Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation. Antioxidants 2023, 12 (2), No. 489. PubMed PMC
Aso K; Kono M; Kanda M; Kudo Y; Sakiyama K; Hisada R; Karino K; Ueda Y; Nakazawa D; Fujieda Y; et al. Itaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming. Nat. Commun 2023, 14 (1), No. 984. PubMed PMC
Mills EL; Ryan DG; Prag HA; Dikovskaya D; Menon D; Zaslona Z; Jedrychowski MP; Costa ASH; Higgins M; Hams E; et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 2018, 556 (7699), 113–117. PubMed PMC
McGettrick AF; Bourner LA; Dorsey FC; O’Neill LAJ Metabolic Messengers: itaconate. Nat. Metab 2024, 6 (9), 1661–1667. PubMed
Hoisnard L; Lebrun-Vignes B; Maury S; Mahevas M; El Karoui K; Roy L; Zarour A; Michel M; Cohen JL; Amiot A; et al. Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database. Sci. Rep 2022, 12 (1), No. 7140. PubMed PMC
Mori S; Ogata F; Tsunoda R. Risk of venous thromboembolism associated with Janus kinase inhibitors for rheumatoid arthritis: case presentation and literature review. Clin. Rheumatol 2021, 40 (11), 4457–4471. PubMed PMC