title: Identification of potent and selective amidobipyridyl inhibitors of protein kinase D.
abstract: The synthesis and biological evaluation of potent and selective PKD inhibitors are described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists. These compounds further establish the central role of PKD as an HDAC4/5 kinase and enhance the current understanding of cardiac myocyte signal transduction. The in vivo efficacy of a representative example compound on heart morphology is reported herein.
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA. erik.meredith@novartis.com
authors.forename: Erik L
authors.initials: EL
authors.lastname: Meredith
authors.forename: Kimberly
authors.initials: K
authors.lastname: Beattie
authors.forename: Robin
authors.initials: R
authors.lastname: Burgis
authors.forename: Michael
authors.initials: M
authors.lastname: Capparelli
authors.forename: Joseph
authors.initials: J
authors.lastname: Chapo
authors.forename: Lucian
authors.initials: L
authors.lastname: Dipietro
authors.forename: Gabriel
authors.initials: G
authors.lastname: Gamber
authors.forename: Istvan
authors.initials: I
authors.lastname: Enyedy
authors.forename: David B
authors.initials: DB
authors.lastname: Hood
authors.forename: Vinayak
authors.initials: V
authors.lastname: Hosagrahara
authors.forename: Charles
authors.initials: C
authors.lastname: Jewell
authors.forename: Keith A
authors.initials: KA
authors.lastname: Koch
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Lemon
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: Dillon
authors.initials: D
authors.lastname: Phan
authors.forename: Craig
authors.initials: C
authors.lastname: Plato
authors.forename: Chang
authors.initials: C
authors.lastname: Rao
authors.forename: Olga
authors.initials: O
authors.lastname: Rozhitskaya
authors.forename: Nicolas
authors.initials: N
authors.lastname: Soldermann
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: Wanlin
authors.initials: W
authors.lastname: Yan
authors.forename: Qingming
authors.initials: Q
authors.lastname: Zhu
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Monovich
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; 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 / Q000493:pharmacokinetics / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy / Q000201:enzymology / 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; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; 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: C551934:2'-cyclohexylamino-6-piperazin-1-yl(2,4')bipyridinyl-4-carboxylic acid amide; D000631:Aminopyridines; D000959:Antihypertensive Agents; D007527:Isoenzymes; D009287:Naphthyridines; D010879:Piperazines; C551933:cyclohexyl-(4-(1-piperazin-1-yl(2,6)naphthyridin-3-yl)pyridin-2-yl)amine; D015082:2,2'-Dipyridyl; C089212:protein kinase D; D011493:Protein Kinase C; D006655:Histone Deacetylases