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

J Med Chem. 2017 Feb 23;60(4):1534-1554. doi: 10.1021/acs.jmedchem.6b01801.

Carolin Schwehm ¹, Barrie Kellam ¹, Aimie E Garces ¹, Stephen J Hill ², Nicholas D Kindon ¹, Tracey D Bradshaw ¹, Jin Li ³, Simon J F Macdonald ⁴, James E Rowedder ⁴, Leigh A Stoddart ², Michael J Stocks ¹

Affiliations

1 School of Pharmacy, Centre for Biomolecular Sciences, University Park Nottingham , Nottingham, NG7 2RD, U.K.
2 Institute of Cell Signalling, Medical School, University of Nottingham , Nottingham, NG7 2UH, U.K.
3 Hitgen Ltd. , F7-10, Building B3, Tianfu Life Science Park, 88 South Kayuan Road, Chengdu, Sichuan, China 610041.
4 GlaxoSmithKline , Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.

PMID: 28128944 DOI: 10.1021/acs.jmedchem.6b01801

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.

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