Identification of orally available naphthyridine protein kinase D inhibitors.
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.
Meredith
Erik L
EL
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Ardayfio
Ophelia
O
Beattie
Kimberly
K
Dobler
Markus R
MR
Enyedy
Istvan
I
Gaul
Christoph
C
Hosagrahara
Vinayak
V
Jewell
Charles
C
Koch
Keith
K
Lee
Wendy
W
Lehmann
Hansjoerg
H
McKinsey
Timothy A
TA
Miranda
Karl
K
Pagratis
Nikos
N
Pancost
Margaret
M
Patnaik
Anup
A
Phan
Dillon
D
Plato
Craig
C
Qian
Ming
M
Rajaraman
Vasumathy
V
Rao
Chang
C
Rozhitskaya
Olga
O
Ruppen
Thomas
T
Shi
Jie
J
Siska
Sarah J
SJ
Springer
Clayton
C
van Eis
Maurice
M
Vega
Richard B
RB
von Matt
Anette
A
Yang
Lihua
L
Yoon
Taeyoung
T
Zhang
Ji-Hu
JH
Zhu
Na
N
Monovich
Lauren G
LG
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
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