ABSTRACT
The design and synthesis of a novel series of 2,6-disubstituted pyrazine derivatives as CK2 kinase inhibitors is described. Structure-guided optimization of a 5-substituted-3-thiophene carboxylic acid screening hit (3a) led to the development of a lead compound (12b), which shows inhibition in both enzymatic and cellular assays. Subsequent design and hybridization efforts also led to the unexpected identification of analogs with potent PIM kinase activity (14f).
Subject(s)
Casein Kinase II/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Pyrazines/pharmacology , Cell Line, Tumor , Drug Design , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Pyrazines/chemical synthesis , Pyrazines/chemistry , Pyrazines/pharmacokinetics , Structure-Activity RelationshipABSTRACT
The design and synthesis of a series of novel tricyclic IAP inhibitors is reported. Rapid assembly of the core tricycle involved two key steps: Rh-catalyzed hydrogenation of an unsaturated bicyclic ring system and a Ru-catalyzed ring closing alkene metathesis reaction. The final Smac mimetics bind to cIAP1 and XIAP BIR3 domains and elicit the desired phenotype in cellular proliferation assays. Dimeric IAP inhibitors were found to possess nanomolar potency in a cellular proliferation assay and favourable in vitro drug-like properties.
Subject(s)
Drug Design , Heterocyclic Compounds, 3-Ring/pharmacology , Inhibitor of Apoptosis Proteins/metabolism , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Inhibitor of Apoptosis Proteins/chemical synthesis , Inhibitor of Apoptosis Proteins/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
Novel substituted benzylidene-1,3-thiazolidine-2,4-diones (TZDs) have been identified as potent and highly selective inhibitors of the PIM kinases. The synthesis and SAR of these compounds are described, along with X-ray crystallographic, anti-proliferative, and selectivity data.
Subject(s)
Benzylidene Compounds/chemistry , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Thiazolidinediones/chemistry , Animals , Benzylidene Compounds/pharmacology , Cell Line , Cell Proliferation/drug effects , Drug Discovery , Humans , Models, Molecular , Protein Kinase Inhibitors/pharmacology , Rats , Structure-Activity Relationship , Thiazolidinediones/pharmacologyABSTRACT
Synthesis and biological evaluation of a series of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors was reported. Biochemical screening, followed by profile optimization, resulted in JAK2 inhibitors exhibiting good kinase selectivity, pharmacokinetic properties, physical properties and pharmacodynamic effects.
Subject(s)
Janus Kinase 2/antagonists & inhibitors , Nitriles/chemical synthesis , Nitriles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyridines/chemistry , Animals , Cell Line , Cell Proliferation/drug effects , Inhibitory Concentration 50 , Mice , Molecular Structure , Nitriles/chemistry , Nitriles/pharmacokinetics , Protein Kinase Inhibitors/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
A series of amidoheteroaryl compounds were designed and synthesized as inhibitors of B-Raf kinase. Several compounds from the series show excellent potency in biochemical, phenotypic and mode of action cellular assays. Potent examples from the series have also demonstrated good plasma exposure following an oral dose in rodents and activity against the Ras-Raf pathway in tumor bearing mice.
Subject(s)
Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Mutation , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Administration, Oral , Animals , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Rats , Structure-Activity Relationship , raf Kinases/metabolism , ras Proteins/metabolismABSTRACT
Neuropeptide Y (NPY) is thought to play a key role in stimulating feeding, thus making NPY receptors attractive appetite suppressant drug targets for treating obesity. Because the orexigenic effects of NPY have been ascribed to actions at the NPY Y5 receptor, we have determined the role of this receptor in feeding in rats, using a small molecule antagonist of this receptor. NPY5RA-972 is a selective and potent (<10 nmol/l) NPY Y5 receptor antagonist. This compound is central nervous system (CNS) penetrant, and an oral dose of 10 mg/kg NPY5RA-972 to rats produced concentrations in cerebrospinal fluid that greatly exceeded the in vitro IC(50) (inhibitory concentration 50%). Indeed, at doses to rats as low as 1 mg/kg, NPY5RA-972 inhibited feeding induced by intracerebroventricular (ICV) administration of a selective NPY Y5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). However, in the dose range 1-10 mg/kg, NPY5RA-972 had no significant effect on food intake in Wistar rats induced to feed by either ICV NPY or 24 h fasting or in free-feeding Wistar or obese Zucker rats. Chronic administration of NPY5RA-972 (10 mg/kg twice daily) had no effect on food intake or body weight in either free-feeding Wistar rats or dietary obese rats. These data indicate that NPY5RA-972 is a potent, selective, orally active, and CNS-penetrant antagonist of the NPY Y5 receptor that prevents feeding driven by activation of this receptor. The data obtained with this antagonist indicate that the NPY Y5 receptor is not a major regulator of feeding in the rat.
Subject(s)
Appetite Depressants/pharmacology , Cyclobutanes/pharmacology , Feeding Behavior/physiology , Neuropeptide Y/pharmacology , Peptide Fragments/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Animals , Appetite Depressants/administration & dosage , Cerebral Ventricles/drug effects , Cerebral Ventricles/physiology , Cyclobutanes/administration & dosage , Energy Intake/drug effects , Feeding Behavior/drug effects , Injections, Intraventricular , Kinetics , Neuropeptide Y/administration & dosage , Peptide Fragments/administration & dosage , Rats , Rats, Wistar , Rats, ZuckerABSTRACT
The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective appetite suppressants for the treatment of obesity has prompted vigorous research to identify suitable compounds. We discovered a series of acylated aminocarbazole derivatives (e.g., 3a) that are potent and selective Y5 antagonists, representing interesting starting points but suffering from poor bioavailability and concerns about potential toxicity as a consequence of the embedded aminocarbazole fragment. It proved relatively easy to improve the drug metabolism and pharmacokinetic (DMPK) properties by variation of the side chain (as in 4a) but difficult to eliminate the aminocarbazole fragment. For compounds in this series to have the potential to be drugs, we believed that both the compound itself and the component aniline must be free of mutagenic activity. Parallel structure-activity relationship studies looking at the effects of ring substitution have proved that it is possible by incorporation of a 4-methyl substituent to produce carbazole ureas with potent Y5 activity, comprised of carbazole anilines that in themselves are devoid of mutagenic activity in the Ames test. Compound 4o (also known as NPY5RA-972) is highly selective with respect to Y1, Y2, and Y4 receptors (and also to a diverse range of unrelated receptors and enzymes), with an excellent DMPK profile including central nervous system penetration. NPY5RA-972 (4o) is a highly potent Y5 antagonist in vivo but does not block neuropeptide Y-induced feeding nor does it reduce feeding in rats, suggesting that the Y5 receptor alone has no significant role in feeding in these models.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Carbazoles/chemical synthesis , Morpholines/chemical synthesis , Receptors, Neuropeptide Y/antagonists & inhibitors , Urea/analogs & derivatives , Urea/chemical synthesis , Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacology , Aniline Compounds/toxicity , Animals , Anti-Obesity Agents/pharmacology , Anti-Obesity Agents/toxicity , Appetite Depressants/chemical synthesis , Appetite Depressants/pharmacology , Appetite Depressants/toxicity , Carbazoles/chemistry , Carbazoles/pharmacology , Carbazoles/toxicity , Dose-Response Relationship, Drug , Eating/drug effects , Fasting , Humans , Morpholines/chemistry , Morpholines/pharmacology , Mutagenicity Tests , Rats , Rats, Wistar , Structure-Activity Relationship , Urea/pharmacology , Urea/toxicityABSTRACT
KIFC1 (HSET), a member of the kinesin-14 family of motor proteins, plays an essential role in centrosomal bundling in cancer cells, but its function is not required for normal diploid cell division. To explore the potential of KIFC1 as a therapeutic target for human cancers, a series of potent KIFC1 inhibitors featuring a phenylalanine scaffold was developed from hits identified through high-throughput screening (HTS). Optimization of the initial hits combined both design-synthesis-test cycles and an integrated high-throughput synthesis and biochemical screening method. An important aspect of this integrated method was the utilization of DMSO stock solutions of compounds registered in the corporate compound collection as synthetic reactants. Using this method, over 1500 compounds selected for structural diversity were quickly assembled in assay-ready 384-well plates and were directly tested after the necessary dilutions. Our efforts led to the discovery of a potent KIFC1 inhibitor, AZ82, which demonstrated the desired centrosome declustering mode of action in cell studies.
Subject(s)
Alanine/analogs & derivatives , Kinesins/antagonists & inhibitors , Pyridines/chemical synthesis , Alanine/chemical synthesis , Alanine/pharmacology , Animals , HeLa Cells , High-Throughput Screening Assays/methods , Humans , Inhibitory Concentration 50 , Mice , Phenylalanine/analogs & derivatives , Pyridines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
In this letter, we describe the design, synthesis, and structure-activity relationship of 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors of CK2 kinase. Property-based optimization of early leads using the 7-oxetan-3-yl amino group led to a series of matched molecular pairs with lower lipophilicity, decreased affinity for human plasma proteins, and reduced binding to the hERG ion channel. Agents in this study were shown to modulate pAKT(S129), a direct substrate of CK2, in vitro and in vivo, and exhibited tumor growth inhibition when administered orally in a murine DLD-1 xenograft.
ABSTRACT
In this paper we describe a series of 3-cyano-5-aryl-7-aminopyrazolo[1,5-a]pyrimidine hits identified by kinase-focused subset screening as starting points for the structure-based design of conformationally constrained 6-acetamido-indole inhibitors of CK2. The synthesis, SAR, and effects of this novel series on Akt signaling and cell proliferation in vitro are described.
ABSTRACT
Trk receptor tyrosine kinases have been implicated in cancer and pain. A crystal structure of TrkA with AZ-23 (1a) was obtained, and scaffold hopping resulted in two 5/6-bicyclic series comprising either imidazo[4,5-b]pyridines or purines. Further optimization of these two fusion series led to compounds with subnanomolar potencies against TrkA kinase in cellular assays. Antitumor effects in a TrkA-driven mouse allograft model were demonstrated with compounds 2d and 3a.
ABSTRACT
The myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are a heterogeneous but related group of hematological malignancies characterized by clonal expansion of one or more myeloid lineages. The discovery of the Jak2 V617F gain of function mutation highlighted Jak2 as a potential therapeutic target in the MPNs. Herein, we disclose the discovery of a series of pyrazol-3-yl pyrimidin-4-amines and the identification of 9e (AZD1480) as a potent Jak2 inhibitor. 9e inhibits signaling and proliferation of Jak2 V617F cell lines in vitro, demonstrates in vivo efficacy in a TEL-Jak2 model, has excellent physical properties and preclinical pharmacokinetics, and is currently being evaluated in Phase I clinical trials.
Subject(s)
Janus Kinase 2/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , STAT Transcription Factors/physiology , Animals , Cell Line, Tumor , Crystallography, X-Ray , Dogs , Female , Humans , In Vitro Techniques , Janus Kinase 2/chemistry , Mice , Mice, Nude , Microsomes, Liver/metabolism , Models, Molecular , Phosphorylation , Protein Conformation , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , STAT Transcription Factors/metabolism , STAT3 Transcription Factor/metabolism , STAT5 Transcription Factor/metabolism , Signal Transduction , Stereoisomerism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Structure-activity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzamides/chemical synthesis , Kinesins/antagonists & inhibitors , Pyrimidinones/chemical synthesis , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Benzamides/pharmacokinetics , Benzamides/pharmacology , Blood Proteins/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Hepatocytes/metabolism , Humans , M Phase Cell Cycle Checkpoints/drug effects , Mice , Mice, Nude , Microsomes, Liver/metabolism , Protein Binding , Pyrimidinones/pharmacokinetics , Pyrimidinones/pharmacology , Rats , Rats, Wistar , Solubility , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The design, synthesis and biological evaluation of a series of 4-aminopyrazolylpyrimidines as potent Trk kinase inhibitors is reported. High-throughput screening identified a promising hit in the 4-aminopyrazolylpyrimidine chemotype. Initial optimization of the series led to more potent Trk inhibitors. Further optimization using two strategies resulted in significant improvement of physical properties and led to the discovery of 10z (AZ-23), a potent, orally bioavailable Trk A/B inhibitor. The compound offers the potential to test the hypothesis that modulation of Trk activity will be of benefit in the treatment of cancer and other indications in vivo.
Subject(s)
Amines/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptor, trkA/antagonists & inhibitors , Animals , Cell Line , Humans , Male , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Rats , Rats, Wistar , Receptor, trkA/chemistry , Receptor, trkA/metabolism , Structure-Activity RelationshipABSTRACT
The solid-supported iodobenzoic acid derivatives 8-10 were coupled with a range of organozinc reagents 1-4 under palladium(o) catalysis. The coupled products released by acidic cleavage with TFA were obtained in high purities after recrystallisation. Analogous coupling of solid-supported (E)- and (Z)-3-iodoacrylic acids 18a, 18b, 19 and 20 gave (E)- and (Z)-alpha,beta-unsaturated acids and amides 21-27 stereospecifically.