Design and elaboration of a tractable tricyclic scaffold to synthesize druglike inhibitors of dipeptidyl peptidase-4 (DPP-4), antagonists of the C–C Chemokine Receptor Type 5 (CCR5), and highly potent and selective phosphoinositol-3 Kinase δ (PI3Kδ) inhibitors

Schwehm, Carolin; Kellam, Barrie; Garces, Aimie; Hill, Stephen J.; Kindon, Nicholas; Bradshaw, Tracey D.; Li, Jin; Macdonald, Simon J.F.; Rowedder, James E.; Stoddart, Leigh A.; Stocks, Michael

Abstract

A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs.

Citation

Schwehm, C., Kellam, B., Garces, A., Hill, S. J., Kindon, N., Bradshaw, T. D., Li, J., Macdonald, S. J., Rowedder, J. E., Stoddart, L. A., & Stocks, M. (2017). Design and elaboration of a tractable tricyclic scaffold to synthesize druglike inhibitors of dipeptidyl peptidase-4 (DPP-4), antagonists of the C–C Chemokine Receptor Type 5 (CCR5), and highly potent and selective phosphoinositol-3 Kinase δ (PI3Kδ) inhibitors. Journal of Medicinal Chemistry, 60(4), https://doi.org/10.1021/acs.jmedchem.6b01801

• Journal Article Type: Article
• Acceptance Date: Jan 26, 2017
• Publication Date: Jan 27, 2017
• Deposit Date: Jul 11, 2017
• Publicly Available Date: Jul 11, 2017
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 60
• Issue: 4
• DOI: https://doi.org/10.1021/acs.jmedchem.6b01801
• Public URL: https://nottingham-repository.worktribe.com/output/838861
• Publisher URL: http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b01801
• Contract Date: Jul 11, 2017