RESUMO
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.
Assuntos
Liases , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Antagonistas de Androgênios , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Glucocorticoides , Humanos , Masculino , Mineralocorticoides , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Esteroide 17-alfa-Hidroxilase , Testosterona , XenobióticosRESUMO
The lasonolides are novel polyketides that have displayed remarkable biological activity in vitro against a variety of cancer cell lines. Herein we describe our first-generation approach to the formal synthesis of lasonolide A. The key findings from these studies ultimately allowed us to go on and complete a total synthesis of lasonolide A. The convergent approach unites two highly complex fragments utilizing a Ru-catalyzed alkene-alkyne coupling. This type of coupling typically generates branched products; however, through a detailed investigation, we are now able to demonstrate that subtle structural changes to the substrates can alter the selectivity to favor the formation of the linear product. The synthesis of the fragments features a number of atom-economical transformations which are highlighted by the discovery of an engineered enzyme to perform a dynamic kinetic reduction of a ß-ketoester to establish the absolute stereochemistry of the southern tetrahydropyran ring with high levels of enantioselectivity.
Assuntos
Antineoplásicos/síntese química , Macrolídeos/síntese química , Alcenos/química , Alcinos/química , Antineoplásicos/química , Catálise , Técnicas de Química Sintética , Cinética , Macrolídeos/química , Rutênio/química , EstereoisomerismoRESUMO
Lasonolide A is a novel polyketide displaying potent anticancer activity across a broad range of cancer cell lines. Here, an enantioselective convergent total synthesis of the (-)-lasonolide A in 16 longest linear and 34 total steps is described. This approach significantly reduces the step count compared to other known syntheses. The synthetic strategy utilizes alkyne-bearing substrates as core building blocks and is highlighted by stitching together two similarly complex halves via a key Ru-catalyzed alkene-alkyne coupling and macrolactionization.
Assuntos
Técnicas de Química Sintética , Macrolídeos/síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Catálise , Macrolídeos/química , Estrutura Molecular , Rutênio/química , EstereoisomerismoRESUMO
Inhibition of TGFß signaling in concert with a checkpoint blockade has been shown to provide improved and durable antitumor immune response in mouse models. However, on-target adverse cardiovascular effects have limited the clinical use of TGFß receptor (TGFßR) inhibitors in cancer therapy. To restrict the activity of TGFßR inhibitors to tumor tissues and thereby widen the therapeutic index, a series of tumor-activated prodrugs of a selective small molecule TGFßR1 inhibitor 1 were prepared by appending 1 to a serine protease substrate and a half-life extension fatty acid carbon chain. The prodrugs were shown to be selectively metabolized in tumor tissues relative to the heart and blood and demonstrated a prolonged favorable increase in the tumor-to-heart ratio of the active drug in tissue distribution studies. Once-weekly administration of the most tissue-selective compound 10 provided anti-tumor efficacy comparable to the parent compound and reduced systemic exposure of the active drug.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/metabolismo , Área Sob a Curva , Estabilidade de Medicamentos , Feminino , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estrutura Molecular , Miocárdio/metabolismo , Neoplasias/metabolismo , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Bibliotecas de Moléculas Pequenas/farmacologia , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
IDO1 inhibitors have shown promise as immunotherapies for the treatment of a variety of cancers, including metastatic melanoma and renal cell carcinoma. We recently reported the identification of several novel heme-displacing IDO1 inhibitors, including the clinical molecules linrodostat (BMS-986205) and BMS-986242. Both molecules contain quinolines that, while being present in successful medicines, are known to be potentially susceptible to oxidative metabolism. Efforts to swap this quinoline with an alternative aromatic system led to the discovery of 2,3-disubstituted pyridines as suitable replacements. Further optimization, which included lowering ClogP in combination with strategic fluorine incorporation, led to the discovery of compound 29, a potent, selective IDO1 inhibitor with robust pharmacodynamic activity in a mouse xenograft model.
RESUMO
Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation.
RESUMO
We identified a novel class of 4-oxo-dihydroquinolines represented by PNU-183792 which specifically inhibit herpesvirus polymerases. PNU-183792 was highly active against human cytomegalovirus (HCMV, IC(50) value 0.69 microM), varicella zoster virus (VZV, IC(50) value 0.37 microM) and herpes simplex virus (HSV, IC(50) value 0.58 microM) polymerases but was inactive (IC(50) value >40 microM) against human alpha (alpha), gamma (gamma), or delta (delta) polymerases. In vitro antiviral activity against HCMV was determined using cytopathic effect, plaque reduction and virus yield reduction assays (IC(50) ranging from 0.3 to 2.4 microM). PNU-183792 antiviral activity against both VZV (IC(50) value 0.1 microM) and HSV (IC(50) ranging from 3 to 5 microM) was analyzed using plaque reduction assays. PNU-183792 was also active (IC(50) ranging 0.1-0.7 microM) in cell culture assays against simian varicella virus (SVV), murine cytomegalovirus (MCMV) and rat cytomegalovirus (RCMV). Cell culture activity was compared with the appropriate licensed drugs ganciclovir (GCV), cidofovir (CDV) and acyclovir (ACV). PNU-183792 was also active against both GCV-resistant and CDV-resistant HCMV and against ACV-resistant HSV. Toxicity assays using four different species of proliferating mammalian cells indicated PNU-183792 was not cytotoxic at relevant drug concentrations (CC(50) value >100 microM). PNU-183792 was inactive against unrelated DNA and RNA viruses indicating specificity for herpesviruses. In animals, PNU-183792 was orally bioavailable and was efficacious in a model of lethal MCMV infection.
Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Infecções por Herpesviridae/tratamento farmacológico , Herpesviridae/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico , Quinolinas/farmacologia , Animais , Antivirais/química , Antivirais/farmacocinética , Linhagem Celular , Farmacorresistência Viral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Herpesviridae/enzimologia , Infecções por Herpesviridae/virologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Muromegalovirus/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
A versatile route to enantiopure 3,3-disubstituted oxindoles and 3a-substituted pyrrolidinoindolines is described in which diastereoselective dialkylation of enantiopure ditriflate 10 with oxindole enolates is the central step. These reactions are rare examples of alkylations of prostereogenic enolates with chiral sp(3) electrophiles that proceed with high facial selectivity (10-20:1). The scope of this method is explored, and a model to rationalize the sense of stereoselection is advanced. This dialkylation chemistry was used to synthesize (-)-phenserine on a multigram scale in six steps and 43% overall yield from 5-methoxy-1,3-dimethyloxindole (27) and to complete a short formal total synthesis of (-)-physostigmine (2).
Assuntos
Indóis/síntese química , Fisostigmina/análogos & derivados , Fisostigmina/síntese química , Pirrolidinas/síntese química , Alquilação , EstereoisomerismoRESUMO
The susceptibility of human cytomegalovirus (CMV) and varicella zoster virus (VZV) clinical isolates to PNU-183792, a 4-oxo-dihydroquinoline, was examined. The antiviral potency of PNU-183792, a non-nucleoside inhibitor, was compared to the licensed nucleoside inhibitors ganciclovir and acyclovir using plaque reduction and virus yield reduction assays. PNU-183792 was as potent against CMV as ganciclovir and was superior in potency to acyclovir against VZV. PNU-183792 represents a new class of non-nucleoside inhibitors of human herpesviruses.
Assuntos
Antivirais/farmacologia , Citomegalovirus/efeitos dos fármacos , Herpesvirus Humano 3/efeitos dos fármacos , Quinolinas/farmacologia , Aciclovir/farmacologia , Linhagem Celular , Citomegalovirus/crescimento & desenvolvimento , Citomegalovirus/isolamento & purificação , Citomegalovirus/fisiologia , Ganciclovir/farmacologia , Herpesvirus Humano 3/crescimento & desenvolvimento , Herpesvirus Humano 3/isolamento & purificação , Herpesvirus Humano 3/fisiologia , Humanos , Técnicas In Vitro , Ensaio de Placa Viral , Replicação Viral/efeitos dos fármacosRESUMO
Crude extracts from the fruiting bodies of Omphalotus illudens displayed activity in the HSV-I/CV-1 antiviral assay. Bioactivity-guided isolation led to the known compound illudin S (1) as the sole antiviral component present in these extracts.
Assuntos
Agaricales/química , Antivirais/isolamento & purificação , Sesquiterpenos/isolamento & purificação , Animais , Antivirais/química , Antivirais/farmacologia , Células Cultivadas/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Haplorrinos , Herpesvirus Humano 1/efeitos dos fármacos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Sesquiterpenos Policíclicos , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
Through broad screening of the compound library at Pharmacia, a naphthalene carboxamide was identified as a nonnucleoside inhibitor of human cytomegalovirus (HCMV) polymerase. Structure-activity relationship studies demonstrated that a quinoline ring could be substituted for naphthalene, resulting in the discovery of a 4-hydroxyquinoline-3-carboxamide (4-HQC) class of antiviral agents with unique biological properties. In vitro assays with the 4-HQCs have demonstrated potent inhibition of HCMV, herpes simplex virus type 1 (HSV-1), and varicella-zoster virus (VZV) polymerases but no inhibition of human alpha, delta, and gamma polymerases. Antiviral cell culture assays have further confirmed that these compounds are active against HCMV, HSV-1, HSV-2, VZV, and many animal herpesviruses. However, these compounds were not active against several nonherpesviruses representing different DNA and RNA virus families. A strong correlation between the viral DNA polymerase and antiviral activity for this class of compounds supports inhibition of the viral polymerase as the mechanism of antiviral activity. Northern blot analysis of immediate-early and late viral transcripts also pointed to a block in the viral life cycle consistent with inhibition of viral DNA replication. In vitro HCMV polymerase assays indicate that the 4-HQCs are competitive inhibitors of nucleoside binding. However, no cross-resistance could be detected with ganciclovir-resistant HCMV or acyclovir-resistant HSV-1 mutants. The unique, broad-spectrum activities of the 4-HQCs may offer new opportunities for treating many of the diseases caused by herpesviruses.