ABSTRACT
The Hedgehog (Hh-) signalling pathway is a key developmental pathway and there is a growing body of evidence showing that this pathway is aberrantly reactivated in a number of human tumors. Novel agents capable of inhibiting this pathway are sought, and an entirely novel series of smoothened (Smo) antagonists capable of inhibiting the pathway have been identified through uHTS screening. Extensive exploration of the scaffold identified the key functionalities necessary for potency, enabling potent nanomolar Smo antagonists like 91 and 94 to be developed. Optimization resulted in the most advanced compounds displaying low serum shift, clean off-targets profile, and moderate clearance in both rats and dogs. These compounds are valuable tools with which to probe the biology of the Hh-pathway.
Subject(s)
Hedgehog Proteins/antagonists & inhibitors , Signal Transduction/drug effects , Urea/pharmacology , Animals , Dogs , Dose-Response Relationship, Drug , Hedgehog Proteins/metabolism , Humans , Microsomes/drug effects , Microsomes/metabolism , Molecular Structure , Rats , Stereoisomerism , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemistryABSTRACT
We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC(50) = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.
Subject(s)
Amides/pharmacology , Drug Discovery , Genes, BRCA1 , Genes, BRCA2 , Indazoles/pharmacology , Mutation , Neoplasms/genetics , Piperidines/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Administration, Oral , Amides/administration & dosage , Amides/chemistry , Amides/pharmacokinetics , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Transformation, Neoplastic , Drug Stability , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Female , Humans , Indazoles/administration & dosage , Indazoles/chemistry , Indazoles/pharmacokinetics , Inhibitory Concentration 50 , Neoplasms/enzymology , Neoplasms/pathology , Piperidines/administration & dosage , Piperidines/chemistry , Piperidines/pharmacokinetics , RatsABSTRACT
A novel series of pyrazolo[1,5-a]quinazolin-5(4H)-one derivatives proved to be a potent class of PARP-1 inhibitors. An extensive SAR around the 3-position of pyrazole in the scaffold led to the discovery of amides derivatives as low nanomolar PARP-1 inhibitors.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Poly(ADP-ribose) Polymerase Inhibitors , Pyrazoles/chemical synthesis , Amides/chemistry , Chemistry, Organic/methods , Chemistry, Pharmaceutical/methods , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacology , HeLa Cells , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Structure , Pyrazoles/pharmacology , Quinazolinones/chemical synthesis , Quinazolinones/pharmacology , Structure-Activity RelationshipABSTRACT
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 microM), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.
