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

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.