RESUMO
The α7 nicotinic acetylcholine receptor is a calcium permeable, ligand-gated ion channel that modulates synaptic transmission in the hippocampus, thalamus, and cerebral cortex. Previously disclosed work described PNU-120596 that acts as a powerful positive allosteric modulator of the α7 nicotinic acetylcholine receptor. The initial structure-activity relationships around PNU-120596 were gleaned from screening a large thiazole library. Independent systematic examination of the aryl and heteroaryl groups resulted in compounds with enhanced potency and improved physico-chemical properties culminating in the identification of 16 (PHA-758454). In the presence of acetylcholine, 16 enhanced evoked currents in rat hippocampal neurons. In a rat model of impaired sensory gating, treatment with 16 led to a reversal of the gating deficit in a dose-dependent manner. These results demonstrate that aryl heteroaryl ureas, like compound 16, may be useful tools for continued exploration of the unique biology of the α7 nicotinic acetylcholine receptor.
Assuntos
Receptores Nicotínicos , Receptor Nicotínico de Acetilcolina alfa7 , Ratos , Animais , Hipocampo , Compostos de Fenilureia/química , Isoxazóis/farmacologia , Isoxazóis/química , Regulação AlostéricaRESUMO
The NCI-60 human tumor cell line panel has proved to be a useful tool for the global cancer research community in the search for novel chemotherapeutics. The publicly available cell line characterization and compound screening data from the NCI-60 assay have significantly contributed to the understanding of cellular mechanisms targeted by new oncology agents. Signature sensitivity/resistance patterns generated for a given chemotherapeutic agent against the NCI-60 panel have long served as fingerprint presentations that encompass target information and the mechanism of action associated with the tested agent. We report the establishment of a new public NCI-60 resource based on the cell line screening of a large and growing set of 175 FDA-approved oncology drugs (AOD) plus >825 clinical and investigational oncology agents (IOA), representing a diverse set (>250) of therapeutic targets and mechanisms. This data resource is available to the public (https://ioa.cancer.gov) and includes the raw data from the screening of the IOA and AOD collection along with an extensive set of visualization and analysis tools to allow for comparative study of individual test compounds and multiple compound sets.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
To facilitate a drug discovery project, we needed to develop a robust asymmetric synthesis of (2S,5S)-5-substituted-azepane-2-carboxylate derivatives. Two key requirements for the synthesis were flexibility for elaboration at C5 and suitability for large scale preparation. To this end we have successfully developed a scalable asymmetric synthesis of these derivatives that starts with known hydroxy-ketone 8. The key step features an oxidative cleavage of aza-bicyclo[3.2.2]nonene 14, which simultaneously generates the C2 and C5 substituents in a stereoselective manner.
Assuntos
Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Descoberta de Drogas , Cetonas/químicaRESUMO
The lack of effective methods to perform direct ß-selective glycosylation reactions with 2-deoxy-1,4-dithio-D-erythro-pentofuranosides has long been a significant stumbling block for the multi-gram synthesis of 4'-thio-2'-deoxy nucleosides. In addition, previously reported methods for the preparation of appropriately substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides have proven problematic for large scale synthesis. To address these issues, herein we describe the modification and optimization of previously reported methods to allow for the convenient large scale synthesis of benzyl substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides. Furthermore, we describe the development of reaction conditions for ß-selective glycosylation reactions of benzyl substituted 2-deoxy-1,4-dithio-D-erythro-pentofuranosides with both N4-benzoylcytosine and 5-aza-cytosine to enable the practical multi-gram syntheses of the clinical candidates 4'-thio-2'-deoxycytidine (T-dCyd) and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd). Taken together, these new synthetic developments have made possible the preclinical and early clinical development of these important anticancer agents at the National Cancer Institute.
Assuntos
Desoxicitidina/química , Desoxicitidina/síntese química , Tetroses/química , Técnicas de Química Sintética , Descoberta de Drogas , GlicosilaçãoRESUMO
In this article, 5-aza-4'-thio-2'-ß-fluoro-2'-deoxycytidine (F-aza-T-dCyd, NSC801845), a novel cytidine analog, is first disclosed and compared with T-dCyd, F-T-dCyd, and aza-T-dCyd in cell culture and mouse xenograft studies in HCT-116 human colon carcinoma, OVCAR3 human ovarian carcinoma, NCI-H23 human NSCLC carcinoma, HL-60 human leukemia, and the PDX BL0382 bladder carcinoma. In three of five xenograft lines (HCT-116, HL-60, and BL-0382), F-aza-T-dCyd was more efficacious than aza-T-dCyd. Comparable activity was observed for these two agents against the NCI-H23 and OVCAR3 xenografts. In the HCT-116 study, F-aza-T-dCyd [10 mg/kg intraperitoneal (i.p.), QDx5 for four cycles], produced complete regression of the tumors in all mice with a response that proved durable beyond postimplant day 150 (129 days after the last dose). Similarly, complete tumor regression was observed in the HL-60 leukemia xenograft when mice were dosed with F-aza-T-dCyd (10 mg/kg i.p., QDx5 for three cycles). In the PDX BL-0382 bladder study, both oral and i.p. dosing of F-aza-T-dCyd (8 mg/kg QDx5 for three cycles) produced regressions that showed tumor regrowth beginning 13 days after dosing. These findings indicate that further development of F-aza-T-dCyd (NSC801845) is warranted. GRAPHICAL ABSTRACT: http://mct.aacrjournals.org/content/molcanther/20/4/625/F1.large.jpg.
Assuntos
Citidina/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Animais , Técnicas de Cultura de Células , Citidina/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel alpha7 nAChR agonist, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (3a, PHA-709829), has been identified for the potential treatment of cognitive deficits in schizophrenia. The compound shows potent and selective alpha7 in vitro activity, excellent brain penetration, good rat oral bioavailability and robust in vivo efficacy in a rat auditory sensory gating model.
Assuntos
Compostos Azabicíclicos/farmacologia , Agonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Benzamidas/farmacologia , Proteínas Sanguíneas/efeitos dos fármacos , Compostos Bicíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Conformação Molecular , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Piridinas/síntese química , Piridinas/química , Quinuclidinas/farmacologia , Ratos , Receptores Muscarínicos/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Receptor Nicotínico de Acetilcolina alfa7RESUMO
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Transtornos Cognitivos/tratamento farmacológico , Agonistas Nicotínicos/síntese química , Nootrópicos/síntese química , Quinuclidinas/síntese química , Receptores Nicotínicos/metabolismo , Esquizofrenia/tratamento farmacológico , Animais , Disponibilidade Biológica , Encéfalo/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Estabilidade de Medicamentos , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Potenciais Evocados Auditivos/efeitos dos fármacos , Humanos , Técnicas In Vitro , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Agonistas Nicotínicos/farmacocinética , Agonistas Nicotínicos/farmacologia , Nootrópicos/farmacocinética , Nootrópicos/farmacologia , Técnicas de Patch-Clamp , Quinuclidinas/química , Quinuclidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Receptor Nicotínico de Acetilcolina alfa7RESUMO
A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new therapeutic agents for the treatment of infections caused by Gram-positive bacteria. Because of their significance, extensive synthetic investigations into the structure-activity relationships of the oxazolidinones have been conducted at Pharmacia. One facet of this research effort has focused on the identification of bioisosteric replacements for the usual oxazolidinone A-ring. In this paper we describe studies leading to the identification of antibacterial agents incorporating a novel isoxazoline A-ring surrogate. In a gratifying result, the initial isoxazoline analogue prepared was found to exhibit in vitro antibacterial activity approaching that of the corresponding oxazolidinone progenitor. The synthesis and antibacterial activity profile of a preliminary series of isoxazoline analogues incorporating either a C-C or N-C linkage between their B- and C-rings will be presented. Many of the analogues exhibited interesting levels of antibacterial activity. The piperazine derivative 54 displayed especially promising in vitro activity and in vivo efficacy comparable to the activity and efficacy of linezolid.
Assuntos
Antibacterianos/síntese química , Derivados de Benzeno/síntese química , Bactérias Gram-Positivas/efeitos dos fármacos , Isoxazóis/síntese química , Piperazinas/síntese química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Disponibilidade Biológica , Cristalografia por Raios X , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/química , Farmacorresistência Bacteriana , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Isoxazóis/química , Isoxazóis/farmacologia , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Piperazinas/química , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/mortalidade , Staphylococcus aureus , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid.
Assuntos
Amidoidrolases/antagonistas & inibidores , Antibacterianos/síntese química , Compostos de Bifenilo/síntese química , Ácidos Hidroxâmicos/síntese química , Éteres Fenílicos/síntese química , Infecções por Pseudomonas/tratamento farmacológico , Sulfetos/síntese química , Sulfonas/síntese química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Domínio Catalítico , Cristalografia por Raios X , Farmacorresistência Bacteriana , Ligação de Hidrogênio , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Camundongos , Modelos Moleculares , Conformação Molecular , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Pseudomonas aeruginosa , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Sulfetos/química , Sulfetos/farmacologia , Sulfonas/química , Sulfonas/farmacologiaRESUMO
The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.
Assuntos
Amidoidrolases/antagonistas & inibidores , Antibacterianos/síntese química , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Ácidos Hidroxâmicos/síntese química , Piridonas/síntese química , Ácidos Sulfônicos/síntese química , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Cristalografia por Raios X , Humanos , Ácidos Hidroxâmicos/farmacocinética , Ácidos Hidroxâmicos/farmacologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/enzimologia , Piridonas/farmacocinética , Piridonas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Ácidos Sulfônicos/farmacocinética , Ácidos Sulfônicos/farmacologiaRESUMO
Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.
Assuntos
Azetidinas/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Cetolídeos/química , Cetolídeos/farmacologia , Infecções Respiratórias/tratamento farmacológico , Animais , Bactérias/efeitos dos fármacos , Infecções Comunitárias Adquiridas/tratamento farmacológico , Suscetibilidade a Doenças , Descoberta de Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Cetolídeos/efeitos adversos , Cetolídeos/síntese química , Cetolídeos/uso terapêutico , Camundongos , Testes de Sensibilidade MicrobianaRESUMO
A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.