title: Discovery of selective and orally available spiro-3-piperidyl ATP-competitive MK2 inhibitors.
abstract: The identification of a potent, selective, and orally available MK2 inhibitor series is described. The initial absence of oral bioavailability was successfully tackled by moving the basic nitrogen of the spiro-4-piperidyl moiety towards the electron-deficient pyrrolepyridinedione core, thereby reducing the pK(a) and improving Caco-2 permeability. The resulting racemic spiro-3-piperidyl analogues were separated by chiral preparative HPLC, and the activity towards MK2 inhibition was shown to reside mostly in the first eluting stereoisomer. This led to the identification of new MK2 inhibitors, such as (S)-23, with low nanomolar biochemical inhibition (EC(50) 7.4 nM) and submicromolar cellular target engagement activity (EC(50) 0.5 μM).
authors.affiliation: Merck Research Laboratories, MSD, Oss, The Netherlands.
authors.forename: Allard
authors.initials: A
authors.lastname: Kaptein
authors.forename: Arthur
authors.initials: A
authors.lastname: Oubrie
authors.forename: Edwin
authors.initials: E
authors.lastname: de Zwart
authors.forename: Niels
authors.initials: N
authors.lastname: Hoogenboom
authors.forename: Joeri
authors.initials: J
authors.lastname: de Wit
authors.forename: Bas
authors.initials: B
authors.lastname: van de Kar
authors.forename: Maaike
authors.initials: M
authors.lastname: van Hoek
authors.forename: Gerard
authors.initials: G
authors.lastname: Vogel
authors.forename: Vera
authors.initials: V
authors.lastname: de Kimpe
authors.forename: Carsten
authors.initials: C
authors.lastname: Schultz-Fademrecht
authors.forename: Judith
authors.initials: J
authors.lastname: Borsboom
authors.forename: Mario
authors.initials: M
authors.lastname: van Zeeland
authors.forename: Judith
authors.initials: J
authors.lastname: Versteegh
authors.forename: Bert
authors.initials: B
authors.lastname: Kazemier
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Roos
authors.forename: Frank
authors.initials: F
authors.lastname: Wijnands
authors.forename: John
authors.initials: J
authors.lastname: Dulos
authors.forename: Martin
authors.initials: M
authors.lastname: Jaeger
authors.forename: Paula
authors.initials: P
authors.lastname: Leandro-Garcia
authors.forename: Tjeerd
authors.initials: T
authors.lastname: Barf
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D013141:Spiro Compounds; D000099190:MAP-Kinase-Activated Kinase 2