ABSTRACT
Pyrrolidine, pyrrolidinone, carbocyclic, and acyclic groups were used as isosteric proline replacements in a series of insulin-like growth factor I receptor kinase/insulin receptor kinase inhibitors. Examples that were similar in potency to proline-containing reference compounds were shown to project a key fluoropyridine amide into a common space, while less potent compounds were not able to do so for reasons of stereochemistry or structural rigidity.
Subject(s)
Proline/chemistry , Protein Kinase Inhibitors/chemistry , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, Insulin/antagonists & inhibitors , Triazines/chemistry , Models, Molecular , Protein Kinase Inhibitors/pharmacology , Triazines/pharmacologyABSTRACT
Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochemical potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626) was selected as a clinical candidate for treatment of solid tumors.
Subject(s)
Antineoplastic Agents/chemical synthesis , Carbamates/chemical synthesis , ErbB Receptors/antagonists & inhibitors , Receptor, ErbB-2/antagonists & inhibitors , Triazines/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Biological Availability , Carbamates/pharmacokinetics , Carbamates/pharmacology , Cell Line, Tumor , Dogs , Drug Screening Assays, Antitumor , Humans , Macaca fascicularis , Mice , Neoplasm Transplantation , Stereoisomerism , Structure-Activity Relationship , Transplantation, Heterologous , Triazines/pharmacokinetics , Triazines/pharmacologyABSTRACT
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
Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.
Subject(s)
Chemistry, Pharmaceutical/methods , ErbB Receptors/chemistry , Neoplasms/drug therapy , Piperidines/chemical synthesis , Pyrroles/chemical synthesis , Receptor, ErbB-2/chemistry , Triazines/chemical synthesis , Adenosine Triphosphate/metabolism , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Design , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Insecta , Models, Chemical , Neoplasm Transplantation , Piperidines/chemistry , Piperidines/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Triazines/chemistry , Triazines/pharmacologyABSTRACT
The identification of a potent series of IKK-beta selective inhibitors based on an imidazothienopyrazine template and the oral efficacy of one such analog (22j) in the LPS-induced TNF-alpha release mouse model are described.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , I-kappa B Kinase/antagonists & inhibitors , Pyrazines/chemistry , Pyrazines/pharmacology , Animals , Cells, Cultured , Enzyme Inhibitors/chemical synthesis , Humans , Mice , Pyrazines/chemical synthesis , Structure-Activity RelationshipABSTRACT
Novel C-5 aminomethyl pyrrolotriazines were prepared and optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The homopiperazine, 1p, emerged as a key lead and it showed promising oral efficacy in EGFR and dual EGFR/HER2 driven human tumor xenograft models. It is hypothesized that the C-5 homopiperazine side chain binds in the ribose-phosphate portion of the ATP binding pocket.
Subject(s)
Antineoplastic Agents/pharmacology , ErbB Receptors/antagonists & inhibitors , Methylamines/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrroles/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Triazines/pharmacology , Animals , Cell Line, Tumor , Disease Models, Animal , Drug Screening Assays, Antitumor , Humans , Methylamines/chemistry , Mice , Models, Molecular , Molecular Structure , Neoplasm Transplantation , Pyrroles/chemistry , Structure-Activity Relationship , Triazines/chemistry , Xenograft Model Antitumor AssaysABSTRACT
Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the ribose phosphate portion of the ATP binding pocket.
Subject(s)
Chemistry, Pharmaceutical/methods , ErbB Receptors/antagonists & inhibitors , Pyrroles/chemical synthesis , Receptor, ErbB-2/antagonists & inhibitors , Triazines/chemical synthesis , Adenosine Triphosphate/chemistry , Animals , Caco-2 Cells , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Mice , Neoplasm Transplantation , Phosphates/chemistry , Pyrroles/pharmacology , Ribose/chemistry , Triazines/pharmacologyABSTRACT
A novel class of 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase is described. This report discusses the SAR of 4-(2-hydroxy-2-phenylethylamino)-substituted pyridones with improved IGF-1R potency.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Insulin-Like Growth Factor I/antagonists & inhibitors , Phosphotransferases/antagonists & inhibitors , Animals , Baculoviridae/enzymology , Cell Line , Cell Proliferation/drug effects , Indicators and Reagents , Mice , Models, Molecular , Pyridones/pharmacology , Structure-Activity Relationship , Thymidine/metabolismABSTRACT
A novel series of dual EGFR and HER2 inhibitors based on the pyrrolo[2,1-f][1,2,4]triazine nucleus is described. A general route toward their synthesis, which enables functionalization at multiple sites, has been developed. Biological evaluation in enzymatic and cell-based assays has identified a series of C-6 carbamates with potent biochemical and cellular activities.
Subject(s)
ErbB Receptors/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor, ErbB-2/antagonists & inhibitors , Binding Sites , Carbamates/chemical synthesis , Carbamates/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Models, Molecular , Structure-Activity Relationship , Triazines/chemical synthesis , Triazines/pharmacologyABSTRACT
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.
Subject(s)
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 AssaysABSTRACT
The evolution of 2, a C-4-methylcarbonate analogue of paclitaxel with minimal oral bioavailability and oral efficacy, into its C-3'-t-butyl-3'-N-t-butyloxycarbonyl analogue (15i), a novel taxane with oral efficacy in preclinical models that is comparable to iv administered paclitaxel, is described.
Subject(s)
Bridged-Ring Compounds/pharmacokinetics , Taxoids/pharmacokinetics , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Biological Availability , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Mice , Rats , Structure-Activity Relationship , Taxoids/chemistry , Taxoids/pharmacologyABSTRACT
The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivatives are described. Modification of the 5'-position led to the discovery of the spirocyclopentyl analogue 7g, which is the first azasordarin to register single-digit MIC values versus Aspergillus spp. Further investigation identified the 5'-i-Pr derivative 7b, which displays superior pharmacokinetic properties compared to other azasordarins.
Subject(s)
Antifungal Agents/chemistry , Antifungal Agents/pharmacokinetics , Aza Compounds/chemical synthesis , Aza Compounds/pharmacokinetics , Administration, Oral , Animals , Antifungal Agents/pharmacology , Aspergillus/drug effects , Aza Compounds/chemistry , Aza Compounds/pharmacology , Glycosides/chemistry , Indenes , Injections, Intravenous , Mice , Microbial Sensitivity Tests , Spiro Compounds/chemistry , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Compounds based on sordaricin were prepared via organometallic addition onto a fully protected sordaricin aldehyde. The fungal growth inhibition profiles for these compounds were established and the results are presented here. The synthesis of homologated sordaricin as well as ether and ester derivatives is presented, and structural rearrangement products upon oxidation. These compounds were evaluated as agents to inhibit fungal growth.
Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Aldehydes/chemical synthesis , Aldehydes/chemistry , Aldehydes/pharmacology , Alkylation , Diterpenes , Fungi/drug effects , Hydrolysis , Indicators and Reagents , Microbial Sensitivity Tests , Oxidation-Reduction , Structure-Activity RelationshipABSTRACT
Core-modified sordaricin derivatives were prepared via biotransformation followed by chemical modification and tested for antifungal activity. The antifungal activity proved to be very sensitive to modifications in the sterics and/or lipophilicity of the diterpene skeleton. Introduction of polar groups such as hydroxyl in the diterpene core results in loss of potency while small and lipophilic groups such as fluorine and the 7,8-olefin are well tolerated.
Subject(s)
Antifungal Agents/metabolism , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Biotransformation , Candida albicans/drug effects , Candida glabrata/drug effects , Diterpenes , Hydrophobic and Hydrophilic Interactions , Microbial Sensitivity Tests , Nocardia/metabolism , StereoisomerismABSTRACT
The synthesis and biological activity of sordarin oxazepine derivatives are described. The key step features a regioselective oxidation of an unprotected triol followed by double reductive amination to afford the ring-closed products. The spectrum of antifungal activity for these novel derivatives includes coverage of Candida albicans, Candida glabrata, and Cryptococcus neoformans.
Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Fungi/drug effects , Oxazepines/chemical synthesis , Oxazepines/pharmacology , Candida albicans/drug effects , Candida glabrata/drug effects , Cryptococcus neoformans/drug effects , Hydrogen Bonding , Indenes , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
Oxime derivatives of the sordarin aglycone have been identified as potent antifungal agents. The in vitro spectrum of activity includes coverage against Candida albicans and Candida glabrata with MICs as low as 0.06 microg/mL. The antifungal activity was established to be exquisitely sensitive to the spatial orientation of the lipophilic side chains.
Subject(s)
Antifungal Agents/chemical synthesis , Oximes/chemical synthesis , Antifungal Agents/pharmacology , Candida/drug effects , Diterpenes , Hydrophobic and Hydrophilic Interactions , Microbial Sensitivity Tests , Oximes/pharmacology , Structure-Activity RelationshipABSTRACT
A fermentation directed product search for potential anticancer drugs conducted by Bristol-Myers in the 1970s and early 1980s resulted in the identification of a novel indolocarbazole (IC) rebeccamycin (RBM) as a potential drug development candidate. Subsequently, an analog program designed to impart distal site in vivo antitumor activity resulted in the discovery of diethylaminoethyl analog of RBM (DEAE-RBM), which is presently undergoing clinical evaluation as NSC 655649 and BMY-27557. Strong DNA intercalation is the primary mechanism of action of DEAE-RBM resulting in the potent catalytic inhibition of both topoisomerases I and II. Precursor feeding fermentation experiments with fluorine-substituted tryptophans yielded novel fluoroindolocarbazoles (FICs). These FICs were identified as targeting topoisomerase (topo) I in a mechanism-based screen and their action on topo I was confirmed by production of topo I-mediated single-strand breaks in DNA at sites essentially identical to those induced by camptothecin. Topo I dependent cytotoxicity was demonstrated for specific FICs using a P388 and camptothecin-resistant P388/CPT45 pair of cell lines, the latter expresses little or no functional topo I. For example, topo I selectivity was greatest with 3,9-difluoro substituted FIC and was least significant and least cytotoxic with 4,8-difluoro substituted FIC. The review focuses on the discovery of the rebeccamycin class of compounds and their structure-activity relationships leading to the development of the clinical candidate BMY-27557 (NSC 655649), as well as the lead identification of the fluoroindolocarbazole class of compounds.
