ABSTRACT
ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5- c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.
Subject(s)
Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Drug Design , Pyridines/pharmacokinetics , Quinolines/pharmacokinetics , Quinolones/pharmacology , Quinolones/pharmacokinetics , Administration, Oral , Ataxia Telangiectasia Mutated Proteins/chemistry , Ataxia Telangiectasia Mutated Proteins/metabolism , Biological Availability , Humans , Inhibitory Concentration 50 , Models, Molecular , Protein Conformation , Protein Kinase Inhibitors , Pyridines/administration & dosage , Pyridines/chemistry , Quinolines/administration & dosage , Quinolines/chemistry , Quinolones/administration & dosage , Quinolones/chemistry , Structure-Activity Relationship , Substrate SpecificityABSTRACT
A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}-3-quinolinecarboxamide (72) and 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (74) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. 72 and 74 constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model.
Subject(s)
Antineoplastic Agents/pharmacology , Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Quinolines/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Ataxia Telangiectasia Mutated Proteins/metabolism , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Mice , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Quinolines/administration & dosage , Quinolines/chemistry , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Optimization of cellular lipophilic ligand efficiency (LLE) in a series of 2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel 2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties. Replacement of the imidazo[1,2-a]pyridine group of the previously reported inhibitor 3 with the related pyrazolo[1,5-a]pyridine improved IGF-1R cellular potency. Substitution of the amino-pyrazole group was key to obtaining excellent kinase selectivity and pharmacokinetic parameters suitable for oral dosing, which led to the discovery of (2R)-1-[4-(4-{[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, 28), a novel, efficacious inhibitor of IGF-1R.
Subject(s)
Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Administration, Oral , Animals , Cell Line , Crystallography, X-Ray , Dose-Response Relationship, Drug , Female , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Receptor, IGF Type 1/metabolism , Structure-Activity RelationshipABSTRACT
A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.
Subject(s)
Estrogen Receptor alpha/metabolism , Umbelliferones/chemistry , Umbelliferones/pharmacology , Administration, Oral , Animals , Cell Line, Tumor , Coumarins/chemistry , Coumarins/pharmacokinetics , Coumarins/pharmacology , Down-Regulation/drug effects , Estrogen Receptor alpha/analysis , Humans , Molecular Docking Simulation , Rats , Umbelliferones/pharmacokineticsABSTRACT
Following the discovery of imidazopyridine 1 as a potent IGF-1R tyrosine kinase inhibitor, the aniline part has been modified with the aim to optimize the properties of this series. The structure-activity relationships against IGF-1R kinase activity as well as inhibition of the hERG ion channel are discussed.
Subject(s)
Aniline Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Drug Discovery , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We disclose a novel series of insulin-like growth factor-1 receptor kinase inhibitors based on the 3-(pyrimidin-4-yl)-imidazo[1,2-a]pyridine scaffold. The influence on the inhibitory activity of substitution on the imidazopyridine and at the C5 position of the pyrimidine is discussed. In the course of this optimization, we discovered a potent and selective inhibitor with suitable pharmacokinetics for oral administration.
Subject(s)
Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Animals , Dogs , Humans , Mice , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship , Tissue DistributionABSTRACT
Optimization of our bis-anilino-pyrimidine series of EphB4 kinase inhibitors led to the discovery of compound 12 which incorporates a key m-hydroxymethylene group on the C4 aniline. 12 displays a good kinase selectivity profile, good physical properties and pharmacokinetic parameters, suggesting it is a suitable candidate to investigate the therapeutic potential of EphB4 kinase inhibitors.
Subject(s)
Aniline Compounds/chemistry , Benzyl Alcohol/chemistry , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Receptor, EphB4/antagonists & inhibitors , Administration, Oral , Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacokinetics , Animals , Benzyl Alcohol/chemical synthesis , Benzyl Alcohol/pharmacokinetics , Binding Sites , Computer Simulation , Crystallography, X-Ray , Drug Evaluation, Preclinical , Mice , Mice, Nude , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Receptor, EphB4/metabolism , Structure-Activity RelationshipABSTRACT
Starting from the initial bis-anilinopyrimidine 1, good potency against EphB4 was retained when benzodioxole at C-4 was replaced by an indazole. The key interactions of the indazole with the protein were characterised by crystallographic studies. Further optimisation led to compound 20, a potent inhibitor of the EphB4 and Src kinases with good pharmacokinetics in various preclinical species and high fraction unbound in plasma. Compound 20 may be used as a tool for evaluating the potential of EphB4 kinase inhibitors in vivo.
Subject(s)
Benzodioxoles/chemical synthesis , Benzodioxoles/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor, EphB4/antagonists & inhibitors , Animals , Benzodioxoles/pharmacokinetics , CHO Cells , Cricetinae , Cricetulus , Crystallography, X-Ray , Dogs , Female , Male , Mice , Mice, Nude , Models, Molecular , Phosphorylation , Protein Kinase Inhibitors/pharmacokinetics , Rats , Rats, Wistar , Structure-Activity Relationship , Substrate Specificity , src-Family Kinases/antagonists & inhibitorsABSTRACT
We have identified a new series of C-5 substituted indazolylaminoquinazolines as potent erbB2 kinase inhibitors. The lead compound 22 showed excellent in vitro potency, good physical properties, acceptable oral pharmacokinetics in rat and dog, and low human in vitro clearance. It showed at least equivalent activity dose for dose compared to lapatinib in various erbB2- or EGFR-driven xenograft models after chronic oral administration.
Subject(s)
Antineoplastic Agents/pharmacology , ErbB Receptors/antagonists & inhibitors , Indazoles/pharmacology , Neoplasms, Experimental/drug therapy , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Dogs , Epidermal Growth Factor/pharmacology , Ether-A-Go-Go Potassium Channels , Female , Hepatocytes/cytology , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Indazoles/chemical synthesis , Keratinocytes/cytology , Keratinocytes/drug effects , Keratinocytes/metabolism , Lapatinib , Male , Metabolic Clearance Rate , Mice , Mice, Nude , Mice, SCID , Microsomes/drug effects , Molecular Structure , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Rats , Rats, Wistar , Survival Rate , Xenograft Model Antitumor AssaysABSTRACT
Novel 4-anilino-1H-pyrazolo[3,4-d]pyrimidines have been synthesized and evaluated in vitro for erbB2 and EGFR kinase inhibition. A representative compound displaying oral bioavailability in rat and dog illustrates the potential of this series to provide orally active erbB2 inhibitors.
Subject(s)
Protein Kinase Inhibitors/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor, ErbB-2/antagonists & inhibitors , Animals , Combinatorial Chemistry Techniques , Dogs , Drug Design , Molecular Structure , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , RatsABSTRACT
Starting from initial lead 1 containing a basic 5-substituent, optimisation of the glycolamide-derived neutral 5-substituent led to potent inhibitors of erbB2 with good pharmacokinetics. Representative compounds 19 and 21 inhibited phosphorylation of erbB2 in a mouse BT474C xenograft model after oral administration.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Animals , Cell Line , Magnetic Resonance Spectroscopy , Mice , Neoplasm Transplantation , Phosphorylation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Quinazolines/administration & dosage , Quinazolines/chemistry , Quinazolines/pharmacokinetics , Structure-Activity RelationshipABSTRACT
[reaction: see text] Two new unsymmetrical 1,2,4,5-tetrazines, 3-methylsulfinyl-6-methylthio-1,2,4,5-tetrazine (4) and 3-(benzyloxycarbonyl)amino-6-methylsulfinyl-1,2,4,5-tetrazine (5), were prepared, and the scope of their participation in intermolecular inverse electron demand Diels-Alder reactions was defined. As anticipated, sulfoxides 4 and 5 (4 > 5) display a reactivity that is substantially greater than that of their corresponding sulfides (2 and 3), being derived from their enhanced electron-deficient character and resulting in a wider range of potential dienophile choices or the use of milder reaction conditions. The cycloaddition reactions were expectedly regioselective, typically producing a single cycloadduct, ensuring their synthetic utility, but both were found to proceed with a regioselectivity opposite what would be anticipated and complementary to that observed with 2 and 3.
