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
The Hedgehog (Hh-) signaling pathway is a key developmental pathway which gets reactivated in many human tumors, and smoothened (Smo) antagonists are emerging as novel agents for the treatment of malignancies dependent on the Hh-pathway, with the most advanced compounds demonstrating encouraging results in initial clinical trials. A novel series of potent bicyclic hydantoin Smo antagonists was reported in the preceding article, these have been resolved, and optimized to identify potent homochiral derivatives with clean off-target profiles and good pharmacokinetic properties in preclinical species. While showing in vivo efficacy in mouse allograft models, unsubstituted bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-diones were shown to epimerize in plasma. Alkylation of the C-8 position blocks this epimerization, resulting in the identification of MK-5710 (47) which was selected for further development.
Subject(s)
Antineoplastic Agents/chemistry , Hedgehog Proteins/antagonists & inhibitors , Imidazoles/chemistry , Pyrazines/chemistry , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Dogs , Hedgehog Proteins/metabolism , Humans , Imidazoles/pharmacology , Imidazoles/therapeutic use , Mice , Neoplasms/drug therapy , Pyrazines/pharmacology , Pyrazines/therapeutic use , Rats , Signal Transduction/drug effects , Stereoisomerism , 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 genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Indoles/chemical synthesis , Oxazocines/chemical synthesis , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Biological Availability , Cell Line, Tumor , Crystallography, X-Ray , Dogs , Hepacivirus/enzymology , Hepacivirus/physiology , Humans , Indoles/pharmacokinetics , Indoles/pharmacology , Macaca mulatta , Mice , Mice, SCID , Mice, Transgenic , Models, Molecular , Molecular Structure , Oxazocines/pharmacokinetics , Oxazocines/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Viremia/drug therapy , Viremia/virology , Virus Replication/drug effectsABSTRACT
5-Aryl-2-(trifluoroacetyl)thiophenes were identified as a new series of class II HDAC inhibitors (HDACi). Further development of this new series led to compounds such as 6h, a potent inhibitor of HDAC4 and HDAC6 (HDAC4 WT IC(50) = 310 nM, HDAC6 IC(50) = 70 nM) that displays 40-fold selectivity over HDAC1 and improved stability in HCT116 cancer cells (t(1/2) = 11 h). Compounds 6h and 2 show inhibition of alpha-tubulin deacetylation in HCT116 cells at 1 microM concentration and antiproliferation effects only at concentrations where inhibition of histone H3 deacetylation is observed.
Subject(s)
Antineoplastic Agents/chemical synthesis , Histone Deacetylase 2/antagonists & inhibitors , Repressor Proteins/antagonists & inhibitors , Thiophenes/chemical synthesis , Acetylation , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Histone Deacetylase 1/antagonists & inhibitors , Histone Deacetylase 6 , Histone Deacetylases/metabolism , Histones/metabolism , Humans , Isoenzymes/antagonists & inhibitors , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacology , Tubulin/metabolismABSTRACT
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
In a follow-up to our recent disclosure of P2-P4 macrocyclic inhibitors of the hepatitis C virus (HCV) NS3 protease (e.g., 1, Chart 1), we report a new but related compound series featuring a basic amine at the N-terminus of the P3-amino acid residue. Replacement of the electroneutral P3-amino acid capping group (which is a feature of almost all tripeptide-like inhibitors of NS3 reported to date) with a basic group is not only tolerated but can result in advantageous cell based potency. Optimization of this new class of P3-amine based inhibitors gave compounds such as 25 and 26 that combine excellent cell based activity with pharmacokinetic properties that are attractive for an antiviral targeting HCV.
Subject(s)
Amines/chemical synthesis , Antiviral Agents/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Amines/pharmacokinetics , Amines/pharmacology , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Dogs , Drug Discovery , Male , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
PARP inhibitors have been demonstrated to retard intracellular DNA repair and therefore sensitize tumor cells to cytotoxic agents or ionizing radiation. We report the identification of a novel class of PARP1 inhibitors, containing a pyrrolo moiety fused to a dihydroisoquinolinone, derived from virtual screening of the proprietary collection. SAR exploration around the nitrogen of the aminoethyl appendage chain of 1 led to compounds that displayed low nanomolar activity in a PARP1 enzymatic assay.
Subject(s)
Poly(ADP-ribose) Polymerase Inhibitors , Quinolones/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , DNA Repair , Drug Design , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Ligands , Models, Chemical , Polymers/chemistry , Structure-Activity RelationshipABSTRACT
We report the synthesis and biological evaluation of N-[(1-aryl-1H-indazol-5-yl)methyl]amide derivatives as Smoothened antagonists and inhibitors of the Hedgehog pathway. Identification of the lead structure 1 by HTS, followed by SAR study on the amide and aryl portions led to the discovery of antagonists with nanomolar activity.
Subject(s)
Amides/chemical synthesis , Indazoles/chemical synthesis , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/chemistry , Amides/pharmacology , Catalysis , Cell Line , Chemistry, Pharmaceutical/methods , Combinatorial Chemistry Techniques/methods , Drug Design , Drug Evaluation, Preclinical , Humans , Indazoles/pharmacology , Inhibitory Concentration 50 , Models, Chemical , Signal Transduction , Smoothened Receptor , Structure-Activity RelationshipABSTRACT
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
Trifluoroacetylthiophene carboxamides have recently been reported to be class II HDAC inhibitors, with moderate selectivity. Exploration of replacements for the carboxamide with bioisosteric pentatomic heteroaromatic like 1,3,4-oxadiazoles, 1,2,4-oxadiazoles and 1,3-thiazoles, led to the discovery that 2-trifluoroacetylthiophene 1,3,4-oxadiazole derivatives are very potent low nanomolar HDAC4 inhibitors, highly selective over class I HDACs (HDAC 1 and 3), and moderately stable in HCT116 cell culture.
Subject(s)
Histone Deacetylase Inhibitors , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Combinatorial Chemistry Techniques , Drug Design , HCT116 Cells , Histone Acetyltransferases/antagonists & inhibitors , Histone Deacetylases/classification , Humans , Molecular Structure , Oxadiazoles/chemistry , Structure-Activity Relationship , Thiophenes/chemistryABSTRACT
A series of aryltetrazolylacetanilides was synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors on wild-type virus and on the clinically relevant K103N mutant strain. Extensive SAR investigation led to potent compounds, with nanomolar activity on K103N, and orally bioavailable in rats.