ABSTRACT
Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compounds in in vivo studies.
Subject(s)
Amides/pharmacology , Piperazines/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Smoothened Receptor , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination.
Subject(s)
BRCA1 Protein/deficiency , Piperazines/chemical synthesis , Poly(ADP-ribose) Polymerase Inhibitors , Pyridazines/chemical synthesis , Animals , BRCA1 Protein/genetics , HeLa Cells , Humans , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Piperazines/metabolism , Piperazines/pharmacology , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerases/metabolism , Pyridazines/metabolism , Pyridazines/pharmacology , RatsABSTRACT
The optimization of a potent, class I selective ketone HDAC inhibitor is shown. It possesses optimized pharmacokinetic properties in preclinical species, has a clean off-target profile, and is negative in a microbial mutagenicity (Ames) test. In a mouse xenograft model it shows efficacy comparable to that of vorinostat at a 10-fold reduced dose.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Histone Deacetylase Inhibitors , Quinolines/pharmacokinetics , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Dogs , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , HeLa Cells , Humans , Mice , Quinolines/chemical synthesis , RatsABSTRACT
Heat shock protein 90 (Hsp90) is a molecular chaperone necessary for maintaining oncogenic transformation. There is substantial interest in developing novel agents that bind to the N-terminal of the chaperone. Here we report the synthesis and characterization of two fluorescent Hsp90 inhibitors and probe their use in an Hsp90 fluorescent polarization assay.
