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Publication Abstract from PubMed

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.

Discovery of an Oral, Rule of 5 Compliant, Interleukin 17A Protein-Protein Interaction Modulator for the Potential Treatment of Psoriasis and Other Inflammatory Diseases.,Andrews MD, Dack KN, de Groot MJ, Lambert M, Sennbro CJ, Larsen M, Stahlhut M J Med Chem. 2022 Jul 14;65(13):8828-8842. doi: 10.1021/acs.jmedchem.2c00422. Epub, 2022 Jun 29. PMID:35767390^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.