Design of Potent mRNA Decapping Scavenger Enzyme (DcpS) Inhibitors with Improved Physicochemical Properties To Investigate the Mechanism of Therapeutic Benefit in Spinal Muscular Atrophy (SMA)

• Published in: Journal of medicinal chemistry Vol. 60; no. 7; pp. 3094 - 3108
• Main Authors: Gopalsamy, Ariamala, Narayanan, Arjun, Liu, Shenping, Parikh, Mihir D, Kyne, Robert E, Fadeyi, Olugbeminiyi, Tones, Michael A, Cherry, Jonathan J, Nabhan, Joseph F, LaRosa, Gregory, Petersen, Donna N, Menard, Carol, Foley, Timothy L, Noell, Stephen, Ren, Yong, Loria, Paula M, Maglich-Goodwin, Jodi, Rong, Haojing, Jones, Lyn H
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13-04-2017
• Subjects: Animals; Disease Models, Animal; Drug Design; Endoribonucleases - antagonists & inhibitors; Endoribonucleases - genetics; Endoribonucleases - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; HEK293 Cells; Humans; Mice; Molecular Docking Simulation; Muscular Atrophy, Spinal - drug therapy; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - metabolism; Quinazolines - chemistry; Quinazolines - pharmacokinetics; Quinazolines - pharmacology; Quinazolines - therapeutic use; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - genetics; Survival of Motor Neuron 2 Protein
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00124

The C-5 substituted 2,4-diaminoquinazoline RG3039 (compound 1), a member of a chemical series that was identified and optimized using an SMN2 promoter screen, prolongs survival and improves motor function in a mouse model of spinal muscular atrophy (SMA). It is a potent inhibitor of the mRNA decapping scavenger enzyme (DcpS), but the mechanism whereby DcpS inhibition leads to therapeutic benefit is unclear. Compound 1 is a dibasic lipophilic molecule that is predicted to accumulate in lysosomes. To understand if the in vivo efficacy is due to DcpS inhibition or other effects resulting from the physicochemical properties of the chemotype, we undertook structure based molecular design to identify DcpS inhibitors with improved physicochemical properties. Herein we describe the design, synthesis, and in vitro pharmacological characterization of these DcpS inhibitors along with the in vivo mouse CNS PK profile of PF-DcpSi (compound 24), one of the analogs found to be efficacious in SMA mouse model.