2. Academic Validation
  3. 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)

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)

  • J Med Chem. 2017 Apr 13;60(7):3094-3108. doi: 10.1021/acs.jmedchem.7b00124.
Ariamala Gopalsamy 1 2,  Arjun Narayanan 1 2,  Shenping Liu 1 2,  Mihir D Parikh 1 2,  Robert E Kyne Jr 1 2,  Olugbeminiyi Fadeyi 1 2,  Michael A Tones 1 2,  Jonathan J Cherry 1 2,  Joseph F Nabhan 1 2,  Gregory LaRosa 1 2,  Donna N Petersen 1 2,  Carol Menard 1 2,  Timothy L Foley 1 2,  Stephen Noell 1 2,  Yong Ren 1 2,  Paula M Loria 1 2,  Jodi Maglich-Goodwin 1 2,  Haojing Rong 1 2,  Lyn H Jones 1 2
Affiliations

Affiliations

  • 1 Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.
  • 2 Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
PMID: 28257199 DOI: 10.1021/acs.jmedchem.7b00124
Abstract

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.

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