title: Tetrahydropyrrolo-diazepenones as inhibitors of ERK2 kinase.
abstract: A series of structure based drug design hypotheses and focused screening efforts led to the identification of tetrahydropyrrolo-diazepenones with striking potency against ERK2 kinase. The role of fluorination in mitigating microsomal clearance was systematically explored. Ultimately, it was found that fluorination of a cyclopentanol substructure provided significant improvement in both potency and human metabolic stability.
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Ave., Cambridge, MA 02139, USA. Electronic address: jeffrey.bagdanoff@novartis.com.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Bagdanoff
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton St., Building 4, Emeryville, CA 94608, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Jain
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton St., Building 4, Emeryville, CA 94608, USA.
authors.forename: Wooseok
authors.initials: W
authors.lastname: Han
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton St., Building 4, Emeryville, CA 94608, USA.
authors.forename: Shejin
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton St., Building 4, Emeryville, CA 94608, USA.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Madiera
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton St., Building 4, Emeryville, CA 94608, USA.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Lee
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton St., Building 4, Emeryville, CA 94608, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Ma
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton St., Building 4, Emeryville, CA 94608, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Poon
mesh_terms: D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D006574:Heterocyclic Compounds, 2-Ring; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D019950:Mitogen-Activated Protein Kinase 1
keywords: ATP binding cleft; ERK2 kinase; Extraction ratio; Lower-hinge lysine; Structure based drug design