ABSTRACT
Long-acting (LA) human immunodeficiency virus-1 (HIV-1) antiretroviral therapy characterized by a ≥1 month dosing interval offers significant advantages over daily oral therapy. However, the criteria for compounds that enter clinical development are high. Exceptional potency and low plasma clearance are required to meet dose size requirements; excellent chemical stability and/or crystalline form stability is required to meet formulation requirements, and new antivirals in HIV-1 therapy need to be largely free of side effects and drug-drug interactions. In view of these challenges, the discovery that capsid inhibitors comprising a quinazolinone core tolerate a wide range of structural modifications while maintaining picomolar potency against HIV-1 infection in vitro, are assembled efficiently in a multi-component reaction, and can be isolated in a stereochemically pure form is reported herein. The detailed characterization of a prototypical compound, GSK878, is presented, including an X-ray co-crystal structure and subcutaneous and intramuscular pharmacokinetic data in rats and dogs.
Subject(s)
Anti-HIV Agents , HIV Infections , HIV-1 , Humans , Rats , Animals , Dogs , Capsid , Capsid Proteins , Quinazolinones/pharmacology , Quinazolinones/therapeutic use , Anti-HIV Agents/pharmacokinetics , HIV Infections/drug therapyABSTRACT
We report herein, the discovery of BMS-737 (compound 33) as a potent, non-steroidal, reversible small molecule inhibitor demonstrating 11-fold selectivity for CYP17 lyase over CYP17 hydroxylase, as well as a clean xenobiotic CYP profile for the treatment of castration-resistant prostate cancer (CRPC). Extensive SAR studies on the initial lead 1 at three different regions of the molecule resulted in the identification of BMS-737, which demonstrated a robust 83% lowering of testosterone without any significant perturbation of the mineralocorticoid and glucocorticoid levels in cynomologous monkeys in a 1-day PK/PD study.
Subject(s)
Lyases , Prostatic Neoplasms, Castration-Resistant , Prostatic Neoplasms , Androgen Antagonists , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Glucocorticoids , Humans , Male , Mineralocorticoids , Prostatic Neoplasms, Castration-Resistant/drug therapy , Steroid 17-alpha-Hydroxylase , Testosterone , XenobioticsABSTRACT
Allosteric HIV-1 integrase inhibitors (ALLINIs) have been of interest recently because of their novel mechanism of action. Strategic modifications to the C5 moiety of a class of 4-(4,4-dimethylpiperidinyl)-2,6-dimethylpyridinyl ALLINIs led to the identification of a tetrahydroisoquinoline heterocycle as a suitable spacer element to project the distal hydrophobic aryl ring. Subsequent optimization of the aryl substitutions identified 12 as an ALLINI with single-digit nanomolar inhibitory potency and low clearance across preclinical species. In preclinical toxicology studies with 12 in rats, lipid hepatocellular vacuolation was observed. Removal of the C6 methyl group resulted in GSK3839919 (22), which exhibited a reduced incidence and severity of lipid vacuolation in both in vitro assays and in vivo studies while maintaining the potency and pharmacokinetic (PK) properties of the prototype. The virology, PK, and toxicology profiles of 22 are discussed.
ABSTRACT
The 60 individual halopyridine isomers that contain one bromine, chlorine, fluorine, iodine, and H are valuable potential building blocks in medicinal chemistry research, but surprisingly, there has been only one report on the synthesis of just two of them. Herein, we describe simple syntheses of the unique 5-bromo-2-chloro-4-fluoro-3-iodopyridine (10) and 3-bromo-6-chloro-4-fluoro-2-iodopyridine (32) using halogen dance reactions. C6 magnesiation of 10 and its 3-phenyl analogue 22 followed by trapping with electrophiles generated a variety of pentasubstituted pyridines with desired functionalities for further chemical manipulations.
Subject(s)
Halogens , Iodine , Bromine , Chlorine , PyridinesABSTRACT
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
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
The SAR of PXR transactivation by 3-(benzimidazol-2-yl)-pyridine-2-one based ATP competitive inhibitors of Insulin-like Growth Factor 1 Receptor kinase (IGF-1R) is discussed. Compounds without PXR transactivation, with in vivo antitumor activity, reduced protein binding and improved oral exposure are presented.
Subject(s)
Antineoplastic Agents/chemistry , Benzimidazoles/chemistry , Protein Kinase Inhibitors/chemistry , Receptor, IGF Type 1/antagonists & inhibitors , Receptors, Steroid/genetics , Transcriptional Activation , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacokinetics , Cell Line, Tumor , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Humans , Mice , Mice, Nude , Pregnane X Receptor , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Receptor, IGF Type 1/metabolism , Receptors, Steroid/metabolism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Generation of imino-quinone methide type intermediates from 2-aminothiazole-5-carbinols using alkylsulfonic acids in nitromethane followed by trapping with a wide range of nucleophiles effects C-C, C-O, C-N, C-S, and C-P bond formation.
Subject(s)
Imines/chemistry , Indolequinones/chemical synthesis , Methanol/analogs & derivatives , Thiazoles/chemistry , Indolequinones/chemistry , Methanol/chemistry , Molecular Structure , StereoisomerismABSTRACT
This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.
Subject(s)
Biomedical Research , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Triazines/pharmacology , Animals , Dogs , Drug Discovery , Humans , Mice , Models, Molecular , Molecular Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Rats , Receptor, IGF Type 1/chemistry , Structure-Activity Relationship , Triazines/chemistry , Triazines/pharmacokinetics , Triazines/therapeutic useABSTRACT
We previously reported that 1 (BMS-536924), a benzimidazole inhibitor of the insulin-like growth factor-1 receptor, had demonstrated in vivo antitumor activity. This lead compound was found to have potent CYP3A4 inhibition, CYP3A4 induction mediated by PXR transactivation, poor aqueous solubility, and high plasma protein binding. Herein we disclose the evolution of this chemotype to address these issues. This effort led to 10 (BMS-695735), which exhibits improved ADME properties, a low risk for drug-drug interactions, and in vivo efficacy in multiple xenograft models.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Benzimidazoles/administration & dosage , Benzimidazoles/pharmacology , Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Pyridones/administration & dosage , Pyridones/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Benzimidazoles/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP3A Inhibitors , Drug Screening Assays, Antitumor , Humans , Mice , Mice, Nude , Molecular Structure , Neoplasm Transplantation , Pregnane X Receptor , Protein Kinase Inhibitors/chemistry , Pyridones/chemistry , Receptors, Steroid/drug effects , Receptors, Steroid/metabolism , Solubility , Stereoisomerism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
3-(Benzimidazol-2-yl)-pyridine-2-one-based ATP competitive inhibitors of Insulin-like Growth Factor 1 Kinase (IGF-IR) were optimized for reduced Cyp3A4 inhibition and improved oral exposure. The use of malonate as methyl anion synthon via S(N)Ar reaction and double decarboxylation under mild conditions is demonstrated.
Subject(s)
Benzimidazoles/pharmacology , Cytochrome P-450 CYP3A Inhibitors , Receptor, IGF Type 1/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Administration, Oral , Area Under Curve , Chemistry, Pharmaceutical/methods , Cytochrome P-450 CYP3A/chemistry , Drug Design , Fluorine/chemistry , Humans , Inhibitory Concentration 50 , Models, Chemical , Nitrogen/chemistry , Receptor, IGF Type 1/chemistry , Somatomedins/chemistry , Thymidine/chemistryABSTRACT
A series of IGF-1R inhibitors is disclosed, wherein the (m-chlorophenyl)ethanol side chain of BMS-536924 (1) is replaced with a series of 2-(1H-imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chains. Some analogs show improved IGF-1R potency and oral exposure. Analogs from both series, 16a and 17f, show in vivo activity comparable to 1 in our constitutively activated IGF-1R Sal tumor model. This may be the due to the improved protein binding in human and mouse serum for imidazole 16a and the excellent oral exposure of pyrazole 17f.
Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Pyridones/chemistry , Pyridones/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Humans , Mice , Molecular Structure , Neoplasms, Experimental/drug therapy , Protein Binding , Serum , Structure-Activity RelationshipABSTRACT
The insulin-like growth factor receptor (IGF-IR) and insulin receptor are either overactivated and/or overexpressed in a wide range of tumor types and contribute to tumorigenicity, proliferation, metastasis, and drug resistance. Here, we show that BMS-554417, a novel small molecule developed as an inhibitor of IGF-IR, inhibits IGF-IR and insulin receptor kinase activity and proliferation in vitro, and reduces tumor xenograft size in vivo. In a series of carcinoma cell lines, the IC50 for proliferation ranged from 120 nmol/L (Colo205) to >8.5 micromol/L (OV202). The addition of stimulatory ligands was unnecessary for the antiproliferative effect in MCF-7 and OV202 cells. BMS-554417 treatment inhibited IGF-IR and insulin receptor signaling through extracellular signal-related kinase as well as the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased Akt phosphorylation at Ser473. At doses that inhibited proliferation, the compound also caused a G0-G1 arrest and prevented nuclear accumulation of cyclin D1 in response to LR3 IGF-I. In Jurkat T-cell leukemia cells, this agent triggered apoptotic cell death via the mitochondrial pathway. BMS-554417 was orally bioavailable and significantly inhibited the growth of IGF1R-Sal tumor xenografts in vivo. BMS-554417 is a member of a novel class of IGF-IR/insulin receptor inhibitors that have potential clinical applications because of their antiproliferative and proapoptotic activity in vitro and in vivo.
Subject(s)
Piperazines/pharmacology , Pyridones/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, Insulin/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Caspases/metabolism , Cell Growth Processes/drug effects , Cell Line, Tumor , Cell Nucleus/metabolism , Cyclin D1/metabolism , Dose-Response Relationship, Drug , Enzyme Activation , Female , G1 Phase/drug effects , Humans , Insulin-Like Growth Factor I/antagonists & inhibitors , Mice , Mice, Nude , Mitochondria/drug effects , Mitochondria/physiology , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinase Kinases/metabolism , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Receptor, IGF Type 1/metabolism , Receptor, Insulin/metabolism , S Phase/drug effectsABSTRACT
Compound 3 (BMS-536924), a novel small-molecule inhibitor of the insulin-like growth factor receptor kinase with equal potency against the insulin receptor is described. The in vitro and in vivo biological activity of this interesting compound is also reported.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzimidazoles/chemical synthesis , Pyridines/chemical synthesis , Pyridones/chemical synthesis , Receptor, IGF Type 1/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Biological Availability , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Haplorhini , Humans , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Neoplasm Transplantation , Pyridines/chemistry , Pyridines/pharmacology , Pyridones/chemistry , Pyridones/pharmacology , Rats , Receptor, Insulin/drug effects , Structure-Activity RelationshipABSTRACT
The insulin-like growth factor I receptor (IGF-IR) is a transmembrane tyrosine kinase that is essential to growth and development and also thought to provide a survival signal for the maintenance of the transformed phenotype. There has been increasing interest in further understanding the role of IGF-I signaling in cancer and in developing receptor antagonists for therapeutic application. We describe herein a novel animal model that involves transgenic expression of a fusion receptor that is constitutively activated by homodimerization. Transgenic mice that expressed the activated receptor showed aberrant development of the mammary glands and developed salivary and mammary adenocarcinomas as early as 8 weeks of age. Xenograft tumors and a cell line were derived from the transgenic animals and are sensitive to inhibition by a novel small-molecule inhibitor of the IGF-IR kinase. This new model should provide new opportunities for further understanding how aberrant IGF-IR signaling leads to tumorigenesis and for optimizing novel antagonists of the receptor kinase.
Subject(s)
Adenocarcinoma/genetics , Cell Transformation, Neoplastic/genetics , Mammary Neoplasms, Experimental/genetics , Receptor, IGF Type 1/biosynthesis , Salivary Gland Neoplasms/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Animals , CD8 Antigens/biosynthesis , CD8 Antigens/genetics , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Female , Humans , Mammary Neoplasms, Experimental/enzymology , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred ICR , Mice, Nude , Mice, Transgenic , Neoplasm Transplantation , Pregnancy , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, IGF Type 1/genetics , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/genetics , Salivary Gland Neoplasms/enzymology , Salivary Gland Neoplasms/pathology , Transfection , Transgenes/genetics , Transplantation, HeterologousABSTRACT
A series of fluoroglycosylated fluoroindolocarbazoles was examined with respect to their topoisomerase I activity, cytotoxicity, and selectivity. The lead clinical candidate from this series, BMS-250749, displays broad spectrum antitumor activity superior to CPT-11 against some preclinical xenograft models, including curative antitumor activity against Lewis lung carcinoma.
Subject(s)
Antineoplastic Agents/chemical synthesis , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Carbazoles/chemical synthesis , Glucosides/chemical synthesis , Indoles/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Carbazoles/chemistry , Carbazoles/pharmacology , Cell Line, Tumor , Drug Evaluation, Preclinical , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Glucosides/chemistry , Glucosides/pharmacology , Humans , In Vitro Techniques , Indoles/chemistry , Indoles/pharmacology , Irinotecan , Mice , Microsomes, Liver/metabolism , Topoisomerase I Inhibitors , Transplantation, HeterologousABSTRACT
[reaction: see text] Both 6'- and 4'-fluoro-glycosylated indolo[2,3-a]carbazoles are substrates for base-induced loss of fluorine as a leaving group from sp3 carbon. In the case of alpha-N-glycosylated substrate 3, loss of fluorine from the 6'-position leads to 3,6-anhydroglucose analogue 1. A novel N12,N13-bridged sugar analogue 2 results from loss of 4'-fluorine from beta-N-glycosylated analogue 4. Both analogues 1 and 2 display topo I inhibitory potencies similar to camptothecin.
Subject(s)
Carbazoles/chemical synthesis , Carbon/chemistry , Enzyme Inhibitors/chemical synthesis , Fluorine/chemistry , Glycosides/chemical synthesis , Heterocyclic Compounds, Bridged-Ring/chemical synthesis , Hydrocarbons, Fluorinated/chemical synthesis , Indoles/chemical synthesis , Topoisomerase I Inhibitors , Animals , Carbazoles/pharmacology , Enzyme Inhibitors/pharmacology , Glycosides/pharmacology , Heterocyclic Compounds, Bridged-Ring/pharmacology , Hydrocarbons, Fluorinated/chemistry , Indoles/chemistry , Leukemia P388 , Molecular Conformation , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.
