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.
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.
Halogens , Iodine , Bromine , Chlorine , Pyridines
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.
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 Assays
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.
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 Assays
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.
Imines/chemistry , Indolequinones/chemical synthesis , Methanol/analogs & derivatives , Thiazoles/chemistry , Indolequinones/chemistry , Methanol/chemistry , Molecular Structure , Stereoisomerism
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.
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/chemistry
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.
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 Relationship
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.
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 effects
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.
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 Relationship
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.
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, Heterologous
[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.
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 Relationship
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.
Antineoplastic Agents/chemical synthesis , Carbazoles/chemical synthesis , Glucosides/chemical synthesis , Prostatic Neoplasms/drug therapy , Topoisomerase I Inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Carbazoles/chemistry , Carbazoles/pharmacology , Glucosides/chemistry , Glucosides/pharmacology , Male , Mice , Neoplasm Transplantation , Solubility , Structure-Activity Relationship , Water , Xenograft Model Antitumor Assays
