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Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo.

Lorthiois E, Anderson K, Vulpetti A, Rogel O, Cumin F, Ostermann N, Steinbacher S, Mac Sweeney A, Delgado O, Liao SM, Randl S, Rüdisser S, Dussauge S, Fettis K, Kieffer L, de Erkenez A, Yang L, Hartwieg C, Argikar UA, La Bonte LR, Newton R, Kansara V, Flohr S, Hommel U, Jaffee B, Maibaum J
J Med Chem 60 5717-5735 (2017)
Related entries: 5nar, 5nat, 5naw, 5nb7, 5nba

Cited: 13 times
EuropePMC logo PMID: 28621538

Abstract

The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.

Reviews citing this publication (7)

  1. Complement System and Potential Therapeutics in Age-Related Macular Degeneration. Park YG, Park YS, Kim IB. Int J Mol Sci 22 6851 (2021)
  2. Low-molecular weight inhibitors of the alternative complement pathway. Schubart A, Flohr S, Junt T, Eder J. Immunol Rev 313 339-357 (2023)
  3. Targeting the Complement Cascade for Treatment of Dry Age-Related Macular Degeneration. Patel PN, Patel PA, Land MR, Bakerkhatib-Taha I, Ahmed H, Sheth V. Biomedicines 10 1884 (2022)
  4. Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway. Barratt J, Weitz I. Front Immunol 12 712572 (2021)
  5. Complement Inhibition Therapy and Dialytic Strategies in Paroxysmal Nocturnal Hemoglobinuria: The Nephrologist's Opinion. Gembillo G, Siligato R, Cernaro V, Santoro D. J Clin Med 9 (2020)
  6. Novel Insights into Factor D Inhibition. Gavriilaki E, Papakonstantinou A, Agrios KA. Int J Mol Sci 23 7216 (2022)
  7. Recent Advances in Indazole-Containing Derivatives: Synthesis and Biological Perspectives. Zhang SG, Liang CG, Zhang WH. Molecules 23 (2018)

Articles citing this publication (6)

  1. Base-Promoted Intramolecular Addition of Vinyl Cyclopropanecarboxamides to Access Conformationally Restricted Aza[3.1.0]bicycles. Li J, Zhang Z, Chen L, Li M, Zhang X, Zhang G. Molecules 28 3691 (2023)
  2. Complement system and age-related macular degeneration: drugs and challenges. Wu J, Sun X. Drug Des Devel Ther 13 2413-2425 (2019)
  3. Discovery and Design of First Benzylamine-Based Ligands Binding to an Unlocked Conformation of the Complement Factor D. Vulpetti A, Ostermann N, Randl S, Yoon T, Mac Sweeney A, Cumin F, Lorthiois E, Rüdisser S, Erbel P, Maibaum J. ACS Med Chem Lett 9 490-495 (2018)
  4. Exploring Prognostic Biomarkers of Acute Myeloid Leukemia to Determine Its Most Effective Drugs from the FDA-Approved List through Molecular Docking and Dynamic Simulation. Alom MM, Faruqe MO, Molla MKI, Rahman MM. Biomed Res Int 2023 1946703 (2023)
  5. Incidence of Anaplastic Large Cell Lymphoma and Breast-Implant-Associated Lymphoma-An Analysis of a Certified Tumor Registry over 17 Years. Prantl L, Gerken M, Zeman F, Leitzmann M, Koller M, Klinkhammer-Schalke M, Evert M, Kuehlmann B, Biermann N. J Clin Med 9 (2020)
  6. [How I diagnose and treat paroxysmal nocturnal hemoglobinuria]. Fu R. Zhonghua Xue Ye Xue Za Zhi 39 887-891 (2018)


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