Discovery of a novel class of targeted kinase inhibitors that blocks protein kinase C signaling and ameliorates retinal vascular leakage in a diabetic rat model.
Protein kinase C (PKC) family members such as PKCbetaII may become activated in the hyperglycemic state associated with diabetes. Preclinical and clinical data implicate aberrant PKC activity in the development of diabetic microvasculature abnormalities. Based on this potential etiological role for PKC in diabetic complications, several therapeutic PKC inhibitors have been investigated in clinical trials for the treatment of diabetic patients. In this report, we present the discovery and preclinical evaluation of a novel class of 3-amino-pyrrolo[3,4-c]pyrazole derivatives as inhibitors of PKC that are structurally distinct from the prototypical indolocarbazole and bisindolylmaleimide PKC inhibitors. From this pyrrolo-pyrazole series, several compounds were identified from biochemical assays as potent, ATP-competitive inhibitors of PKC activity with high specificity for PKC over other protein kinases. These compounds were also found to block PKC signaling activity in multiple cellular functional assays. PF-04577806, a representative from this series, inhibited PKC activity in retinal lysates from diabetic rats stimulated with phorbol myristate acetate. When orally administered, PF-04577806 showed good exposure in the retina of diabetic Long-Evans rats and ameliorated retinal vascular leakage in a streptozotocin-induced diabetic rat model. These novel PKC inhibitors represent a promising new class of targeted protein kinase inhibitors with potential as therapeutic agents for the treatment of patients with diabetic microvascular complications.
Department of Biochemistry and Primary Screening, Pfizer Global Research & Development, Pfizer La Jolla Laboratories, San Diego, CA 92121, United States. stephan.grant@pfizer.com
Stephan
S
Grant
Phong
P
Tran
Qin
Q
Zhang
Aihua
A
Zou
Dac
D
Dinh
Jordan
J
Jensen
Sue
S
Zhou
Xiaolin
X
Kang
Joseph
J
Zachwieja
John
J
Lippincott
Kevin
K
Liu
Sarah Ludlum
SL
Johnson
Stephanie
S
Scales
Chunfeng
C
Yin
Seiji
S
Nukui
Chad
C
Stoner
Ganesh
G
Prasanna
Jennifer
J
Lafontaine
Peter
P
Wells
Hui
H
Li
D000284:Administration, Oral; D000818:Animals; D002417:Cattle; D002460:Cell Line; D048909:Diabetes Complications / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D004195:Disease Models, Animal; D055808:Drug Discovery; D006801:Humans; D008297:Male; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012164:Retinal Diseases / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D012171:Retinal Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D013379:Substrate Specificity
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D011493:Protein Kinase C