Structure-Based Drug Design of RN486, a Potent and Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis

Abstract

Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.

Pyrrolo[2,3-b]pyridine derivatives as potent Bruton’s tyrosine kinase inhibitors

“…11 Overall, 3p should demonstrate a higher enzyme potency compared to 1, which is consistent with the SAR study.…”

“…9 Several BTK inhibitors also demonstrated efficacy in animal models of rheumatoid arthritis (RA). [10][11][12][13][14] However, only a few of these inhibitors have entered clinical trials for RA.…”

“…Superimposed models of 3p and 1 (RN486) revealed similar docking poses of the two compounds(Figure 2A).Figure 2Bshows that the entire molecule of 3p was favorably located in the BTK pocket, as expected. The N atom in the 1'-position and N-H group in the 7'-position of pyrrolo[2,3-b]pyridine led to the conservation of key bidentate hydrogen bonding interactions with Met477 11,15. This has also been confirmed by the results of SAR studies that the closely related indole derivative 3v without N atom in the 1'-position displayed no BTK inhbitory activity (IC 50 > 5000 nM…”

Design and synthesis of carbazole carboxamides as promising inhibitors of Bruton’s tyrosine kinase (BTK) and Janus kinase 2 (JAK2)

“…Although the 4-substituents of compounds 29-35 are similar to substituents in previously reported BTK inhibitors, [21][22][23] it is doubtful that these substituents play the same role in enzyme potency and selectivity in the carbazole series. In the earlier-reported cases, BTK potency is exquisitely sensitive to the presence of the tert-butylphenyl (or a similar group): replacement by a simple unsubstituted benzamide 22 or acetamide 21 leads to dramatic loss of potency (575-fold and 1420-fold, respectively).…”

“…Indeed, complete removal of the benzamide moiety (compound 11) causes only a 2-fold change in potency compared to 32. Additionally, the extended conformation reported for the imidazopyrazine, pyrazinone and pyridinone series, [21][22][23] where the tert-butylphenyl occupies the socalled H3 pocket, is thought to be important for both potency and selectivity, but this conformation is unlikely in the carbazole series. The presence of the tricyclic ring system would destabilize this extended conformation through steric clash between the carbazole core and the 4-phenyl substituent, as suggested by the near-orthogonal arrangement observed in the X-ray structure of 13.…”