ABSTRACT
The synthesis and structure-activity relationships of a novel aryl uracil series which contains a fused 5,6-bicyclic ring unit for HCV NS5B inhibition is described. Several analogs display replicon cell culture potencies in the low nanomolar range along with excellent rat pharmacokinetic values.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Uracil/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Hepacivirus/enzymology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/metabolism , Rats , Structure-Activity Relationship , Uracil/pharmacology , Viral Nonstructural Proteins/metabolismABSTRACT
Pharmacological targeting of the dopamine D4 receptor (D4R)âexpressed in brain regions that control cognition, attention, and decision-makingâcould be useful for several neuropsychiatric disorders including substance use disorders (SUDs). This study focused on the synthesis and evaluation of a novel series of benzothiazole analogues designed to target D4R. We identified several compounds with high D4R binding affinity (Ki ≤ 6.9 nM) and >91-fold selectivity over other D2-like receptors (D2R, D3R) with diverse partial agonist and antagonist profiles. Novel analogue 16f is a potent low-efficacy D4R partial agonist, metabolically stable in rat and human liver microsomes, and has excellent brain penetration in rats (AUCbrain/plasma > 3). 16f (5-30 mg/kg, i.p.) dose-dependently decreased iv cocaine self-administration in rats, consistent with previous results produced by D4R-selective antagonists. Off-target antagonism of 5-HT2A or 5-HT2B may also contribute to these effects. Results with 16f support further efforts to target D4R in SUD treatment.
Subject(s)
Cocaine , Substance-Related Disorders , Humans , Animals , Rats , Serotonin , Benzothiazoles/pharmacology , Benzothiazoles/therapeutic use , Brain , Cocaine/pharmacologyABSTRACT
The design and synthesis of indazolinone containing kinase inhibitors are reported. Regioisomers that showed profound potency variation in previously-reported isoindolinone and aminoindazole systems were surprisingly found to have similar potencies in the case of the indazolinone chemical series. An interpretation using differential hinge hydrogen bonding and tautomeric equilibrium of indazolinone ring system is supported by quantum mechanics calculations. The equipotent inhibition of a representative kinase (KDR) by regioisomeric indazolinones 4 and 5 is clear evidence that in case of the indazolinone hinge, both tautomers are equally favored, and should be considered in design of inhibitors.
Subject(s)
Indazoles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Indazoles/pharmacology , Isomerism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A high throughput screening (HTS) hit, 1 (Plk1 K(i)=2.2 µM) was optimized and evaluated for the enzymatic inhibition of Plk-1 kinase. Molecular modeling suggested the importance of adding a hydrophobic aromatic amine side chain in order to improve the potency by a classic kinase H-donor-acceptor binding mode. Extensive SAR studies led to the discovery of 49 (Plk1 K(i)=5 nM; EC(50)=1.05 µM), which demonstrated moderate efficacy at 100 mpk in a MiaPaCa tumor model, with no overt toxicity.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Cycle Proteins/antagonists & inhibitors , High-Throughput Screening Assays , Neoplasms, Experimental/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Models, Molecular , Molecular Structure , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Polo-Like Kinase 1ABSTRACT
Four hinge-binding scaffolds have been explored for novel selective Aurora kinase inhibitors. The structure activity relationship, selectivity and pharmacokinetic profiles have been evaluated.
Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Aurora Kinases , Cell Line , Mice , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.
Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/chemistry , Pyrimidines/chemistry , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Amination , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aurora Kinase B , Aurora Kinases , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Models, Molecular , Molecular Structure , Pyrimidines/pharmacology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
In an effort to identify multi-targeted kinase inhibitors with a novel spectrum of kinase activity, a screen of Abbott proprietary KDR inhibitors against a broad panel of kinases was conducted and revealed a series of thienopyridine ureas with promising activity against the Aurora kinases. Modification of the diphenyl urea and C7 moiety of these compounds provided potent inhibitors with good pharmacokinetic profiles that were efficacious in mouse tumor models after oral dosing. Compound 2 (ABT-348) of this series is currently undergoing Phase I clinical trials in solid and hematological cancer populations.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Urea/pharmacology , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Humans , Mice , Protein Kinase Inhibitors/chemistry , Vascular Endothelial Growth Factor AABSTRACT
In an effort to discover Aurora kinase inhibitors, an HTS hit revealed an amide containing pyrrolopyrimidine compound. Replacement of the pyrrolopyrimidine residue with a thienopyrimidine moiety led to a series of potent and selective Aurora inhibitors.
Subject(s)
Drug Discovery , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , Animals , Aurora Kinases , Dose-Response Relationship, Drug , High-Throughput Screening Assays , Hydrogen Bonding , Mice , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of quinoline derivatives was synthesized as potential bioisosteric replacements for the benzothiadiazine moiety of earlier Hepatitis C NS5B polymerase inhibitors. Several of these compounds exhibited potent activity in enzymatic and replicon assays.
Subject(s)
Benzothiadiazines/pharmacology , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Benzothiadiazines/chemistry , Hepacivirus/enzymology , Hepacivirus/physiology , Protease Inhibitors/chemistry , Virus ReplicationABSTRACT
The design and enzyme activities of a novel class of imidazo[2,1-b]thiazoles is presented.
Subject(s)
ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Thiazoles/pharmacology , Models, Molecular , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
The ectodomain of HIV-1 gp41 mediates the fusion of viral and host cellular membranes. The peptide-based drug Enfuvirtide(1) is precedent that antagonists of this fusion activity may act as anti HIV-agents. Here, NMR screening was used to discover non-peptide leads against this target and resulted in the discovery of a new benzamide 1 series. This series is non-peptide, low molecular weight, and analogs have activity in a cell fusion assay with EC50 values ranging 3-41microM. Structural work on the gp41/benzamide 1 complex was determined by NMR spectroscopy using a designed model peptide system that mimics an open pocket of the fusogenic form of the protein.
Subject(s)
Anti-HIV Agents/chemistry , Benzamides/chemistry , HIV Envelope Protein gp41/chemistry , HIV Fusion Inhibitors/chemistry , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Crystallography, X-Ray , Enfuvirtide , HIV Envelope Protein gp41/metabolism , HIV Envelope Protein gp41/pharmacology , HIV Fusion Inhibitors/chemical synthesis , HIV Fusion Inhibitors/pharmacology , Humans , Magnetic Resonance Spectroscopy , Models, Molecular , Peptide Fragments/chemistry , Peptide Fragments/pharmacology , Protein Binding , Structure-Activity RelationshipABSTRACT
A series of benzoisoxazoles and benzoisothiazoles have been synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs). Structure-activity relationship studies led to the identification of 3-amino benzo[ d]isoxazoles, incorporating a N, N'-diphenyl urea moiety at the 4-position that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor families of RTKs. Within this series, orally bioavailable compounds possessing promising pharmacokinetic profiles were identified, and a number of compounds demonstrated in vivo efficacy in models of VEGF-stimulated vascular permeability and tumor growth. In particular, compound 50 exhibited an ED 50 of 2.0 mg/kg in the VEGF-stimulated uterine edema model and 81% inhibition in the human fibrosarcoma (HT1080) tumor growth model when given orally at a dose of 10 mg/kg/day.
Subject(s)
Isoxazoles/chemical synthesis , Models, Molecular , Oxazoles/chemical synthesis , Phenylurea Compounds/chemical synthesis , Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Binding Sites , Biological Availability , Capillary Permeability/drug effects , Cell Line , Cell Line, Tumor , Edema/drug therapy , Female , Humans , Isoxazoles/pharmacokinetics , Isoxazoles/pharmacology , Mice , Mice, Inbred BALB C , NIH 3T3 Cells , Oxazoles/pharmacokinetics , Oxazoles/pharmacology , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/pharmacology , Phosphorylation , Structure-Activity Relationship , Uterus/blood supply , Xenograft Model Antitumor AssaysABSTRACT
A series of isoxazolo[3,4-b]quinoline-3,4(1H,9H)-diones were synthesized as potent inhibitors against Pim-1 and Pim-2 kinases. The structure-activity-relationship studies started from a high-throughput screening hit and was guided by molecular modeling of inhibitors in the active site of Pim-1 kinase. Installing a hydroxyl group on the benzene ring of the core has the potential to form a key hydrogen bond interaction to the hinge region of the binding pocket and thus resulted in the most potent inhibitor, 19, with K(i) values at 2.5 and 43.5 nM against Pim-1 and Pim-2, respectively. Compound 19 also exhibited an activity profile with a high degree of kinase selectivity.
Subject(s)
Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Models, Molecular , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Quinolines/chemical synthesis , Quinolines/pharmacology , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Humans , Isoxazoles/chemistry , Molecular Conformation , Molecular Structure , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
We report the discovery of the pyrimido-diazepine scaffolds as novel adenine mimics. Structure-based design led to the discovery of analogs with potent inhibitory activity against receptor tyrosine kinases, such as KDR, Flt3 and c-Kit. Compound 14 exhibited low nanomolar KDR enzymatic and cellular potencies (IC(50)=9 and 52 nM, respectively).
Subject(s)
Azepines/chemical synthesis , Azepines/pharmacology , Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , 3T3 Cells , Animals , Azepines/chemistry , Hydrogen Bonding , Mice , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Receptor Protein-Tyrosine Kinases/chemistry , Receptor Protein-Tyrosine Kinases/metabolism , Structure-Activity RelationshipABSTRACT
4,4-Dialkyl-1-hydroxy-3-oxo-3.4-dihydronaphthalene-3-yl benzothiadiazine derivatives were synthesized and evaluated as inhibitors of genotypes 1a and 1b HCV NS5B polymerase. A number of these compounds exhibited potent activity against genotypes 1a and 1b HCV polymerase in both enzymatic and cell culture activities. A representative compound also showed favorable pharmacokinetics in the rat.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Area Under Curve , Chemistry, Pharmaceutical/methods , Drug Design , Genotype , Infusions, Intravenous , Inhibitory Concentration 50 , Models, Chemical , Rats , Viral Nonstructural Proteins/geneticsABSTRACT
Tumor angiogenesis is mediated by KDR and other VEGFR and PDGFR kinases. Their inhibition presents an attractive approach for developing anticancer therapeutics. Here, we report a series of aminopyrazolopyridine ureas as potent VEGFR/PDGFR multitargeted kinase inhibitors. A number of compounds have been identified to be orally bioavailable and efficacious in the mouse edema model.
Subject(s)
Aminopyridines/chemistry , Aminopyridines/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Urea/analogs & derivatives , Administration, Oral , Aminopyridines/chemical synthesis , Aminopyridines/pharmacokinetics , Animals , Biological Availability , Edema/drug therapy , Edema/metabolism , Female , Inhibitory Concentration 50 , Mice , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Structure-Activity Relationship , Urea/chemical synthesis , Urea/pharmacology , Uterine Diseases/drug therapy , Uterine Diseases/metabolismABSTRACT
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.
Subject(s)
Cytosine/analogs & derivatives , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Hepacivirus/enzymology , Stilbenes/chemistry , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Biological Availability , Chemistry Techniques, Synthetic , Cytosine/chemical synthesis , Cytosine/chemistry , Cytosine/pharmacokinetics , Cytosine/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Permeability , Stereoisomerism , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Tissue Distribution , Viral Nonstructural Proteins/chemistryABSTRACT
Based on the crystallographic analysis of a urea-checkpoint kinase 1 (Chk1) complex and molecular modeling, a class of macrocyclic Chk1 inhibitors were designed and their biological activities were evaluated. An efficient synthetic methodology for macrocyclic ureas was developed with Grubbs metathesis macrocyclization as the key step. The structure-activity relationship studies demonstrated that the macrocyclization retains full Chk1 inhibition activity and that the 4-position of the phenyl ring can tolerate a wide variety of substituents. These novel Chk1 inhibitors exhibit excellent selectivity over a panel of more than 70 kinases. Compounds 5b, 5c, 5f, 15, 16d, 17g, 17h, 17k, 18d, and 22 were identified as ideal Chk1 inhibitors, which showed little or no single-agent activity but significantly potentiate the cytotoxicities of the DNA-damaging antitumor agents doxorubicin and camptothecin. These novel Chk1 inhibitors abrogate the doxorubicin-induced G2 and camptothecin-induced S checkpoint arrests, confirming that their potent biological activities are mechanism-based through Chk1 inhibition.
Subject(s)
Antineoplastic Agents/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein Kinases/chemistry , Urea/analogs & derivatives , Urea/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Camptothecin/pharmacology , Cell Line, Tumor , Checkpoint Kinase 1 , Crystallography, X-Ray , DNA Damage , Doxorubicin/pharmacology , Drug Design , Drug Screening Assays, Antitumor , Drug Synergism , Humans , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Models, Molecular , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Structure-Activity Relationship , Urea/chemistry , Urea/pharmacologyABSTRACT
Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment of type 2 diabetes. They exert their beneficial effects by increasing the levels of active glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are two important incretins for glucose homeostasis. Starting from a high-throughput screening hit, we were able to identify a series of piperidinone- and piperidine-constrained phenethylamines as novel DPP4 inhibitors. Optimized compounds are potent, selective, and have good pharmacokinetic profiles.
Subject(s)
Adenosine Deaminase Inhibitors , Dipeptidyl-Peptidase IV Inhibitors , Glycoproteins/antagonists & inhibitors , Phenethylamines/chemical synthesis , Piperidines/chemical synthesis , Animals , Biological Availability , Crystallography, X-Ray , Dipeptidyl Peptidase 4 , Humans , Molecular Conformation , Phenethylamines/pharmacokinetics , Phenethylamines/pharmacology , Piperidines/pharmacokinetics , Piperidines/pharmacology , Piperidones/chemical synthesis , Piperidones/pharmacokinetics , Piperidones/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited a strong ability to abrogate G2 arrest and increased the cytotoxicity of camptothecin by 19-fold against SW620 cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two important binding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, were hydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bond between the methoxy group and Lys38 of the protein.