Discovery and SAR of novel, potent and selective hexahydrobenzonaphthyridinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1).
A novel hexahydrobenzonaphthyridinone PARP-1 pharmacophore is reported, subsequent SAR exploration around this scaffold led to selective PARP-1 inhibitors with low nanomolar enzyme potency, displaying good cellular activity and promising rat PK properties.
Torrisi
Caterina
C
IRBM-Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia, 00040 Rome, Italy. caterina.torrisi@addexpharma.com
Bisbocci
Monica
M
Ingenito
Raffaele
R
Ontoria
Jesus M
JM
Rowley
Michael
M
Schultz-Fademrecht
Carsten
C
Toniatti
Carlo
C
Jones
Philip
P
D000818:Animals; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000378:metabolism; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D009287:Naphthyridines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases