title: Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors.
abstract: A novel series of 2-aminopyridopyrimidinone based JNK (c-jun N-terminal kinase) inhibitors were discovered and developed. Structure-activity relationships (SARs) were systematically developed utilizing biochemical and cell based assays and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies. Through the optimization of lead compound 1, several potent and selective JNK inhibitors with high oral bioavailability were developed. Inhibitor 13 was a potent JNK3 inhibitor (IC50 = 15 nM), had high selectivity against p38 (IC50 > 10 μM), had high potency in functional cell based assays, and had high stability in human liver microsome (t 1/2 = 76 min), a clean CYP-450 inhibition profile, and excellent oral bioavailability (%F = 87). Moreover, cocrystal structures of compounds 13 and 22 in JNK3 were solved at 2.0 Å. These structures elucidated the binding mode (Type-I binding) and can pave the way for further inhibitor design of this pyridopyrimidinone scaffold for JNK inhibition.
authors.affiliation: Medicinal Chemistry, Discovery Biology, Crystallography/Modeling Core Facility, Translational Research Institute, and Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, #2A1, Jupiter, Florida 33458, United States.
authors.forename: Ke
authors.initials: K
authors.lastname: Zheng
authors.affiliation: Medicinal Chemistry, Discovery Biology, Crystallography/Modeling Core Facility, Translational Research Institute, and Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, #2A1, Jupiter, Florida 33458, United States.
authors.forename: Chul Min
authors.initials: CM
authors.lastname: Park
authors.affiliation: Medicinal Chemistry, Discovery Biology, Crystallography/Modeling Core Facility, Translational Research Institute, and Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, #2A1, Jupiter, Florida 33458, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Iqbal
authors.affiliation: Medicinal Chemistry, Discovery Biology, Crystallography/Modeling Core Facility, Translational Research Institute, and Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, #2A1, Jupiter, Florida 33458, United States.
authors.forename: Pamela
authors.initials: P
authors.lastname: Hernandez
authors.affiliation: Medicinal Chemistry, Discovery Biology, Crystallography/Modeling Core Facility, Translational Research Institute, and Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, #2A1, Jupiter, Florida 33458, United States.
authors.forename: HaJeung
authors.initials: H
authors.lastname: Park
authors.affiliation: Medicinal Chemistry, Discovery Biology, Crystallography/Modeling Core Facility, Translational Research Institute, and Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, #2A1, Jupiter, Florida 33458, United States.
authors.forename: Philip V
authors.initials: PV
authors.lastname: LoGrasso
authors.affiliation: Medicinal Chemistry, Discovery Biology, Crystallography/Modeling Core Facility, Translational Research Institute, and Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, #2A1, Jupiter, Florida 33458, United States.
authors.forename: Yangbo
authors.initials: Y
authors.lastname: Feng
keywords: JNK3; Parkinson’s disease (PD); kinase inhibitor; mitochondrial dysfunction; pyridopyrimidinone