ABSTRACT
This letter describes the discovery, synthesis, SAR, and biological activity of [2.2.1]-bicyclic sultams as potent antagonists of the androgen receptor. Optimization of the series led to the identification of compound 25, which displayed robust pharmacodynamic effects in rats after oral dosing.
Subject(s)
Androgen Receptor Antagonists/chemistry , Androgen Receptor Antagonists/pharmacology , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Naphthalenesulfonates/chemistry , Naphthalenesulfonates/pharmacology , Administration, Oral , Androgen Receptor Antagonists/pharmacokinetics , Animals , Bridged Bicyclo Compounds/administration & dosage , Bridged Bicyclo Compounds/pharmacokinetics , Cell Line, Tumor , Humans , Models, Molecular , Naphthalenesulfonates/administration & dosage , Naphthalenesulfonates/pharmacokinetics , Rats , Receptors, Androgen/metabolism , Structure-Activity RelationshipABSTRACT
The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Optimization for JAK family selectivity led to compounds 14 and 21, with greater than 45-fold selectivity for JAK2 over all other members of the JAK kinase family.
Subject(s)
Amides/chemistry , Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Amides/metabolism , Amides/pharmacology , Binding Sites , Carbazoles/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/metabolism , Janus Kinase 2/metabolism , Janus Kinase 3/antagonists & inhibitors , Janus Kinase 3/metabolism , Molecular Dynamics Simulation , Protein Binding , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Structure-Activity RelationshipABSTRACT
This Letter describes synthesis, SAR, and biological activity of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides as inhibitors of γ-secretase mediated signaling of Notch receptors. Optimization of this series led to the identification of BMS-871 (compound 30) which displayed robust in vivo efficacy in Notch-dependent leukemia and solid tumor xenograft models.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Benzodiazepinones/administration & dosage , Benzodiazepinones/pharmacology , Receptors, Notch/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Benzodiazepinones/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Receptors, Notch/metabolism , Structure-Activity RelationshipABSTRACT
A series of aminothiazoles that are potent inhibitors of LIM kinases 1 and 2 is described. Appropriate choice of substituents led to molecules with good selectivity for either enzyme. An advanced member of the series was shown to effectively interfere with the phosphorylation of the LIM kinases substrate cofilin. Consistent with the important role of the LIM kinases in regulating cytoskeletal structure, treated cells displayed dramatically reduced F-actin content.
Subject(s)
Actin Depolymerizing Factors/metabolism , Lim Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Thiazoles/pharmacology , Cell Line , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Lim Kinases/metabolism , Models, Molecular , Molecular Structure , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
Identification, synthesis and structure-activity relationship of small-molecule VIPR1 antagonists encompassing two chemical series are described.
Subject(s)
Antineoplastic Agents/chemical synthesis , Biphenyl Compounds/chemical synthesis , Receptors, Vasoactive Intestinal Polypeptide, Type I/antagonists & inhibitors , Thiophenes/chemical synthesis , Antineoplastic Agents/pharmacology , Biphenyl Compounds/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , High-Throughput Screening Assays , Humans , Receptors, Vasoactive Intestinal Polypeptide, Type I/metabolism , Small Molecule Libraries , Structure-Activity Relationship , Thiophenes/pharmacologyABSTRACT
Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein.
Subject(s)
Pteridines/chemistry , Pyrazines/chemistry , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Half-Life , Pteridines/chemical synthesis , Pteridines/pharmacokinetics , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism , Structure-Activity RelationshipABSTRACT
Therapeutic development of a targeted agent involves a series of decisions over additional activities that may be ignored, eliminated or pursued. This paper details the concurrent application of two methods that provide a spectrum of information about the biological activity of a compound: biochemical profiling on a large panel of kinase assays and transcriptional profiling of mRNA responses. Our mRNA profiling studies used a full dose range, identifying subsets of transcriptional responses with differing EC(50)s which may reflect distinct targets. Profiling data allowed prioritization for validation in xenograft models, generated testable hypotheses for active compounds, and informed decisions on the general utility of the series.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , RNA, Messenger/genetics , Receptor, IGF Type 1/antagonists & inhibitors , Animals , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Colonic Neoplasms/genetics , Cyclin-Dependent Kinase 9/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Humans , Protein Kinase Inhibitors/therapeutic use , Receptor, IGF Type 1/genetics , TriageABSTRACT
The synthesis, evaluation, and structure-activity relationships of a set of related constrained diaminopropane inhibitors of BACE-1 are described. The full in vivo profile of an optimized inhibitor in both normal and P-gp deficient mice is compared with data generated in normal rats.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Diamines/chemistry , Diamines/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Alzheimer Disease/drug therapy , Animals , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/metabolism , Crystallography, X-Ray , Diamines/chemical synthesis , Diamines/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , HEK293 Cells , Humans , Mice , Mice, Knockout , Models, Molecular , Rats , Structure-Activity RelationshipABSTRACT
SAR studies of pyrrolo[1,2-f]triazines as JAK2 inhibitors is presented. Achieving JAK2 inhibition selectively over JAK3 is discussed.
Subject(s)
Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Janus Kinase 2/metabolism , Janus Kinase 3/metabolism , Pyrrolidines/chemical synthesis , Triazines/chemical synthesis , Triazines/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Janus Kinase 2/antagonists & inhibitors , Models, Molecular , Molecular Structure , Protein Binding , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Structure-Activity Relationship , Triazines/chemistryABSTRACT
To selectively target doxorubicin (Dox) to tumor tissue and thereby improve the therapeutic index and/or efficacy of Dox, matrix metalloproteinases (MMP) activated peptide-Dox prodrugs were designed and synthesized by coupling MMP-cleavable peptides to Dox. Preferred conjugates were good substrates for MMPs, poor substrates for neprilysin, an off-target proteinase, and stable in blood ex vivo. When administered to mice with HT1080 xenografts, conjugates, such as 19, preferentially released Dox in tumor relative to heart tissue and prevented tumor growth with less marrow toxicity than Dox.
Subject(s)
Antineoplastic Agents/chemistry , Doxorubicin/analogs & derivatives , Drug Discovery , Matrix Metalloproteinases/chemistry , Prodrugs/chemistry , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Doxorubicin/pharmacology , Drug Discovery/methods , Humans , Matrix Metalloproteinases/pharmacology , Mice , Prodrugs/pharmacology , Xenograft Model Antitumor Assays/methodsABSTRACT
A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.
Subject(s)
Benzimidazoles/chemistry , Piperazines/chemistry , Protein Kinase Inhibitors/chemistry , Pyridones/chemistry , Administration, Oral , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors , Humans , Mice , Mice, Nude , Piperazines/chemical synthesis , Piperazines/pharmacokinetics , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyridones/chemical synthesis , Pyridones/pharmacokinetics , Pyridones/pharmacology , Rats , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, IGF Type 1/metabolism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model.
Subject(s)
Amines/chemistry , Aminopyridines/chemical synthesis , Antineoplastic Agents/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Aminopyridines/chemistry , Aminopyridines/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Cell Line, Tumor , Crystallography, X-Ray , Drug Design , Humans , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/metabolism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3, which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.
Subject(s)
Allosteric Regulation/drug effects , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV-1/drug effects , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Administration, Oral , Animals , Drug Discovery , HIV Infections/drug therapy , HIV Infections/virology , HIV Integrase/metabolism , HIV Integrase Inhibitors/administration & dosage , HIV Integrase Inhibitors/pharmacokinetics , Humans , Male , Molecular Docking Simulation , Pyrazoles/administration & dosage , Pyrazoles/pharmacokinetics , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Rats, Sprague-DawleyABSTRACT
Hit to Lead optimization and SAR development led to the identification of the potent and selective benzo[d]imidazole inhibitor (17b) of Co-activator Associated Arginine Methyltransferase (CARM1).
Subject(s)
Antineoplastic Agents/chemistry , Benzimidazoles/chemistry , Enzyme Inhibitors/chemistry , Piperidines/chemistry , Protein-Arginine N-Methyltransferases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Protein-Arginine N-Methyltransferases/metabolism , Structure-Activity RelationshipABSTRACT
Design, synthesis, and SAR development led to the identification of the potent, novel, and selective pyrazole based inhibitor (7f) of Coactivator Associated Arginine Methyltransferase (CARM1).
Subject(s)
Enzyme Inhibitors/chemistry , Protein-Arginine N-Methyltransferases/antagonists & inhibitors , Pyrazoles/chemistry , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Protein-Arginine N-Methyltransferases/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Structure-Activity RelationshipABSTRACT
Bone remodeling of the auditory ossicles and the otic capsule is highly restricted and tightly controlled by the osteoprotegerin (OPG)/receptor activator of nuclear factor kappa-Β ligand (RANKL)/receptor activator of nuclear factor kappa-Β (RANK) system. In these bony structures, a pathological decrease in OPG expression stimulates osteoclast differentiation and excessive resorption followed by accrual of sclerotic bone, ultimately resulting in the development of otosclerosis, a leading cause of deafness in adults. Understanding the signaling pathways involved in maintaining OPG expression in the ear would shed light on the pathophysiology of otosclerosis and other ear bone-related diseases. We and others previously demonstrated that Ca2+ signaling through the L-type CaV1.2 Ca2+ channel positively regulates OPG expression and secretion in long bone osteoblasts and their precursor cells in vitro and in vivo. Whether CaV1.2 regulates OPG expression in ear bones has not been investigated. We drove expression of a gain-of-function CaV1.2 mutant channel (CaV1.2TS) using Col2a1-Cre, which we found to target osteochondral/osteoblast progenitors in the auditory ossicles and the otic capsule. Col2a1-Cre;CaV1.2TS mice displayed osteopetrosis of these bones shown by µCT 3D reconstruction, histological analysis, and lack of bone sculpting, findings similar to phenotypes seen in mice with an osteoclast defect. Consistent with those observations, we found that Col2a1-Cre;CaV1.2TS mutant mice showed reduced osteoclasts in the otic capsule, upregulated mRNA expression of Opg and Opg/Rankl ratio, and increased mRNA expression of osteoblast differentiation marker genes in the otic capsule, suggesting both an anti-catabolic and anabolic effect of CaV1.2TS mutant channel contributed to the observed morphological changes of the ear bones. Further, we found that Col2a1-Cre;CaV1.2TS mice experienced hearing loss and displayed defects of body balance in behavior tests, confirming that the CaV1.2-dependent Ca2+ influx affects bone structure in the ear and consequent hearing and vestibular functions. Together, these data support our hypothesis that Ca2+ influx through CaV1.2TS promotes OPG expression from osteoblasts, thereby affecting bone modeling/remodeling in the auditory ossicles and the otic capsule. These data provide insight into potential pathological mechanisms underlying perturbed OPG expression and otosclerosis.
Subject(s)
Bone and Bones/metabolism , Calcium Channels, L-Type/metabolism , Calcium Signaling/physiology , Ear, Inner/metabolism , Ear, Middle/metabolism , Animals , Bone Diseases/metabolism , Calcium Channels, L-Type/genetics , Ear Ossicles , Female , Male , Mice , Osteoprotegerin/metabolismABSTRACT
2-Amino-5-(thioaryl)thiazoles are potent inhibitors of TrkA (e.g., 20h, TrkA IC(50)=0.6 nM) that show anti-proliferative effect in cellular assays. A proposed inhibitor binding mode to TrkA active site is consistent with key SAR observations.
Subject(s)
Receptor, trkA/antagonists & inhibitors , Thiazoles/pharmacology , Phosphorylation , Receptor, trkA/metabolism , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure-activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Drug Design , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrroles/pharmacology , Triazines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Angiogenesis Inhibitors/chemical synthesis , Animals , Cell Line , Cytochrome P-450 CYP3A Inhibitors , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Humans , Inhibitory Concentration 50 , Mice , Mice, Inbred BALB C , Pyrroles/chemical synthesis , Structure-Activity Relationship , Triazines/chemical synthesis , Xenograft Model Antitumor AssaysABSTRACT
The CRF antagonist pharmacophore is a heterocyclic ring bearing a critical hydrogen-bond acceptor nitrogen and an orthogonal aromatic ring. CRFR1 antagonists have shown a 40-fold and 200-fold loss in potency against the CRFR1 H199V and M276I mutant receptors, suggesting key interactions with these residues. We have derived a two component computational model that correlates CRFR1 binding affinity within the reported series to antagoinst/H199 complexation energy and M276 hydrophobic contacts.
Subject(s)
Models, Molecular , Pteridines/chemical synthesis , Pyridazines/chemical synthesis , Quantitative Structure-Activity Relationship , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Choroid Plexus/metabolism , Frontal Lobe/metabolism , In Vitro Techniques , Pteridines/chemistry , Pteridines/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacology , Radioligand Assay , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism , SwineABSTRACT
Matrix metalloproteinase (MMP)-activated prodrugs were formed by coupling MMP-cleavable peptides to doxorubicin. The resulting conjugates were excellent in vitro substrates for MMP-2, -9, and -14. HT1080, a fibrosarcoma cell line, was used as a model system to test these prodrugs because these cells, like tumor stromal fibroblasts, expressed several MMPs. In cultured HT1080 cells, simple MMP-cleavable peptides were primarily metabolized by neprilysin, a membrane-bound metalloproteinase. MMP-selective metabolism in cultured HT1080 cells was obtained by designing conjugates that were good MMP substrates but poor neprilysin substrates. To determine how conjugates were metabolized in animals, MMP-selective conjugates were given to mice with HT1080 xenografts and the distribution of doxorubicin was determined. These studies showed that MMP-selective conjugates were preferentially metabolized in HT1080 xenografts, relative to heart and plasma, leading to 10-fold increases in the tumor/heart ratio of doxorubicin. The doxorubicin deposited by a MMP-selective prodrug, compound 6, was more effective than doxorubicin at reducing HT1080 xenograft growth. In particular, compound 6 cured 8 of 10 mice with HT1080 xenografts at doses below the maximum tolerated dose, whereas doxorubicin cured 2 of 20 mice at its maximum tolerated dose. Compound 6 was less toxic than doxorubicin at this efficacious dose because mice treated with compound 6 had no detectable changes in body weight or reticulocytes, a marker for marrow toxicity. Hence, MMP-activated doxorubicin prodrugs have a much higher therapeutic index than doxorubicin using HT1080 xenografts as a preclinical model.