4.7 Article

Discovery of an Oral, Rule of 5 Compliant, Interleukin 17A Protein- Protein Interaction Modulator for the Potential Treatment of Psoriasis and Other Inflammatory Diseases

Journal

JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 13, Pages 8828-8842

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00422

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Funding

  1. LEO Pharma A/S

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This article outlines the research work that led to the identification of 23 as an oral, small-molecule protein-protein interaction modulator (PPIm) clinical development candidate. Protein crystallography provided knowledge of the key binding interactions between small-molecule ligands and the IL-17A dimer, helping in the optimization process towards finding an orally bioavailable, Rule of 5 compliant PPIm of IL-17A.
Interleukin 17A (IL-17A) is an interleukin cytokine whose dysregulation is implicated in autoimmune disorders such as psoriasis, and monoclonal antibodies against the IL-17A pathway are now well-established and very effective treatments. This article outlines the work that led to the identification of 23 as an oral, small-molecule protein-protein interaction modulator (PPIm) clinical development candidate. Protein crystallography provided knowledge of the key binding interactions between small-molecule ligands and the IL-17A dimer, and this helped in the multiparameter optimization toward identifying an orally bioavailable, Rule of 5 compliant PPIm of IL-17A. Overlap of early ligands led to a series of benzhydrylglycine-containing compounds that allowed the identification of dimethylpyrazole as a key substituent that gave PPIm with oral bioavailability. Exploration of the amino acid portion of the structure then led to dicyclopropylalanine as a group that gave potent and metabolically stable compounds, including the development candidate 23.

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