title: 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).
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.
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Ariamala
authors.identifier: 0000-0003-3704-3891
authors.initials: A
authors.lastname: Gopalsamy
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Arjun
authors.initials: A
authors.lastname: Narayanan
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Shenping
authors.initials: S
authors.lastname: Liu
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Mihir D
authors.initials: MD
authors.lastname: Parikh
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Kyne
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Olugbeminiyi
authors.initials: O
authors.lastname: Fadeyi
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Tones
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Cherry
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Nabhan
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Gregory
authors.initials: G
authors.lastname: LaRosa
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Donna N
authors.initials: DN
authors.lastname: Petersen
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Carol
authors.initials: C
authors.lastname: Menard
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Foley
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Noell
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Loria
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jodi
authors.initials: J
authors.lastname: Maglich-Goodwin
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Haojing
authors.initials: H
authors.lastname: Rong
authors.affiliation: Medicine Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Medicine Design and †Primary Pharmacology Group, Pfizer , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Lyn H
authors.identifier: 0000-0002-8388-5865
authors.initials: LH
authors.lastname: Jones
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015195:Drug Design; D004722:Endoribonucleases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D055540:Survival of Motor Neuron 2 Protein; C013474:2,4-diaminoquinazoline; D004722:Endoribonucleases; C485332:DcpS protein, human; C508554:DcpS protein, mouse