Structure Overhaul Affords a Potent Purine PI3Kδ Inhibitor with Improved Tolerability.

Abstract

PI3Kδ catalytic activity is required for immune cell activation, and has been implicated in inflammatory diseases as well as hematological malignancies in which the AKT pathway is overactive. A purine PI3Kδ inhibitor bearing a benzimidazolone-piperidine motif was found to be poorly tolerated in dog, which was attributed to diffuse vascular injury. Several strategies were implemented to mitigate this finding, including reconstruction of the benzimidazolone-piperidine selectivity motif. Structure-based design led to the identification of O- and N-linked heterocycloalkyls, with pyrrolidines being particularly ligand efficient and kinome selective, and having an improved safety pharmacology profile. A representative was advanced into a dog tolerability study where it was found to be well tolerated, with no histopathological evidence of vascular injury.

• Authors: Joey L Methot, Hua Zhou, Sam D Kattar, Meredeth A McGowan, Kevin Wilson, Yudith Garcia, Yongi Deng, Michael Altman, Xavier Fradera, Charles Lesburg, Thierry Fischmann, Chaomin Li, Steve Alves, Sanjiv Shah, Rafael Fernandez, Peter Goldenblatt, Armetta Hill, Lynsey Shaffer, Dapeng Chen, Vince Tong, Robbie L McLeod, Hongshi Yu, Alan Bass, Ray Kemper, Nicholas T Gatto, Lisa LaFranco-Scheuch, Benjamin Wesley Trotter, Timothy Guzi, Jason D Katz
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 9 Pg. 4370-4382 (05 09 2019) ISSN: 1520-4804 [Electronic] United States
• PMID: 30986068 (Publication Type: Journal Article)

Chemical References

• Protein Kinase Inhibitors
• Purines
• Pyrrolidines
• Class Ia Phosphatidylinositol 3-Kinase

Topics

• Animals
• Class Ia Phosphatidylinositol 3-Kinase (metabolism)
• Dogs
• Drug Design
• HeLa Cells
• Humans
• Male
• Protein Kinase Inhibitors (chemical synthesis, pharmacology, toxicity)
• Purines (chemical synthesis, pharmacology, toxicity)
• Pyrrolidines (chemical synthesis, pharmacology, toxicity)
• Rats, Wistar