title: Identification of orally available naphthyridine protein kinase D inhibitors.
abstract: A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart was proposed as a potential antihypertrophic mechanism with application as a heart failure therapy. As PKC was previously identified as the immediate upstream activator of PKD, PKD vs PKC selectivity was essential to understand the effect of PKD inhibition in models of cardiac hypertrophy and heart failure. The present study describes the modification of the HTS hit to a series of prototype pan-PKD inhibitors with routine 1000-fold PKD vs PKC selectivity. Example compounds inhibited PKD activity in vitro, in cells, and in vivo following oral administration. Their effects on heart morphology and function are discussed herein.
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
authors.forename: Erik L
authors.initials: EL
authors.lastname: Meredith
authors.forename: Ophelia
authors.initials: O
authors.lastname: Ardayfio
authors.forename: Kimberly
authors.initials: K
authors.lastname: Beattie
authors.forename: Markus R
authors.initials: MR
authors.lastname: Dobler
authors.forename: Istvan
authors.initials: I
authors.lastname: Enyedy
authors.forename: Christoph
authors.initials: C
authors.lastname: Gaul
authors.forename: Vinayak
authors.initials: V
authors.lastname: Hosagrahara
authors.forename: Charles
authors.initials: C
authors.lastname: Jewell
authors.forename: Keith
authors.initials: K
authors.lastname: Koch
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.forename: Hansjoerg
authors.initials: H
authors.lastname: Lehmann
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
authors.forename: Karl
authors.initials: K
authors.lastname: Miranda
authors.forename: Nikos
authors.initials: N
authors.lastname: Pagratis
authors.forename: Margaret
authors.initials: M
authors.lastname: Pancost
authors.forename: Anup
authors.initials: A
authors.lastname: Patnaik
authors.forename: Dillon
authors.initials: D
authors.lastname: Phan
authors.forename: Craig
authors.initials: C
authors.lastname: Plato
authors.forename: Ming
authors.initials: M
authors.lastname: Qian
authors.forename: Vasumathy
authors.initials: V
authors.lastname: Rajaraman
authors.forename: Chang
authors.initials: C
authors.lastname: Rao
authors.forename: Olga
authors.initials: O
authors.lastname: Rozhitskaya
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruppen
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Siska
authors.forename: Clayton
authors.initials: C
authors.lastname: Springer
authors.forename: Maurice
authors.initials: M
authors.lastname: van Eis
authors.forename: Richard B
authors.initials: RB
authors.lastname: Vega
authors.forename: Anette
authors.initials: A
authors.lastname: von Matt
authors.forename: Lihua
authors.initials: L
authors.lastname: Yang
authors.forename: Taeyoung
authors.initials: T
authors.lastname: Yoon
authors.forename: Ji-Hu
authors.initials: JH
authors.lastname: Zhang
authors.forename: Na
authors.initials: N
authors.lastname: Zhu
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Monovich
mesh_terms: D021581:Active Transport, Cell Nucleus; D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008958:Models, Molecular; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D000959:Antihypertensive Agents; D007527:Isoenzymes; D009287:Naphthyridines; C551933:cyclohexyl-(4-(1-piperazin-1-yl(2,6)naphthyridin-3-yl)pyridin-2-yl)amine; C089212:protein kinase D; D011493:Protein Kinase C; D006655:Histone Deacetylases