Identification of potent and selective amidobipyridyl inhibitors of protein kinase D.
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.
Meredith
Erik L
EL
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA. erik.meredith@novartis.com
Beattie
Kimberly
K
Burgis
Robin
R
Capparelli
Michael
M
Chapo
Joseph
J
Dipietro
Lucian
L
Gamber
Gabriel
G
Enyedy
Istvan
I
Hood
David B
DB
Hosagrahara
Vinayak
V
Jewell
Charles
C
Koch
Keith A
KA
Lee
Wendy
W
Lemon
Douglas D
DD
McKinsey
Timothy A
TA
Miranda
Karl
K
Pagratis
Nikos
N
Phan
Dillon
D
Plato
Craig
C
Rao
Chang
C
Rozhitskaya
Olga
O
Soldermann
Nicolas
N
Springer
Clayton
C
van Eis
Maurice
M
Vega
Richard B
RB
Yan
Wanlin
W
Zhu
Qingming
Q
Monovich
Lauren G
LG
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
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