RESUMO
We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable in vitro profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (15), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when 15 was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of 15 in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.
RESUMO
We describe our efforts to introduce structural diversity to a previously described triazole-containing N1-carboline series of bromodomain and extra-terminal (BET) inhibitors. N9 carbolines were designed to retain favorable binding interactions that the N1-carbolines possess. A convergent synthetic route enabled modifications to reduce clearance, enhance physicochemical properties, and improve the overall in vitro profile. This work led to the identification of a potent BET inhibitor, (S)-2-{8-fluoro-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-7-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-3-yl}propan-2-ol (10), a compound with enhanced oral exposure in mice. Subsequent evaluation in a mouse triple-negative breast cancer tumor model revealed efficacy at 4 mg/kg of N9-carboline 10.
Assuntos
Antineoplásicos/farmacologia , Carbolinas/farmacologia , Desenvolvimento de Medicamentos , Proteínas/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Carbolinas/administração & dosagem , Carbolinas/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Estrutura Molecular , Proteínas/metabolismo , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 "cap" phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12, that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg.
Assuntos
Antineoplásicos/farmacologia , Carbolinas/farmacologia , Desenvolvimento de Medicamentos , Mieloma Múltiplo/dietoterapia , Proteínas/antagonistas & inibidores , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbolinas/síntese química , Carbolinas/química , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Mieloma Múltiplo/metabolismo , Proteínas/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
Chemical oxidation is a key technique used in dye wastewater treatment via the formation of hydroxyl radicals. To obtain optimal treatment effects, it is critical to understand the interaction of the molecular structure of the dye with the hydroxyl radical. We evaluated fluorescence excitation-emission matrix spectroscopy to study the decay of an azo-dye (Procion Red MX-5B) by a hydroxyl radical generated from catalytic Fe (III) on H2O2. Results showed that fluorescence signal reliably indicated the variations of the chemical groups and components during degradation, and the degradation could be divided into three stages: initial degradation (decolorisation), rapid intermediate degradation, and final degradation. Under control of uncorrected matrix correlation, the fluorescence fractions could be fitted successfully by parallel factor model (PARAFAC) model: two fluorescence components in initial degradation including mono substituted benzene and mono substituted naphthalene, three components as multi substituted benzene in rapid degradation, and no components could be resolved in the final degradation. The results from the study demonstrate the utility fluorescence characterization of dye degradation mechanisms and enhance the understanding of the degradation mechanisms.
Assuntos
Corantes/química , Catálise , Compostos Férricos/química , Peróxido de Hidrogênio/química , Radical Hidroxila/síntese química , Radical Hidroxila/química , Estrutura Molecular , Oxirredução , Espectrometria de Fluorescência , Águas Residuárias/químicaRESUMO
Indole- and azaindole-based glyoxylyl amide derivatives have been described as HIV-1 attachment inhibitors (AIs) that act by blocking the interaction between the viral gp120 coat protein and the human host cell CD4 receptor. As part of an effort to more deeply understand the role of the indole/azaindole heterocycle in the expression of antiviral activity, a survey of potential replacements was conducted using parallel synthesis methodology. The design and optimization was guided by a simple 2-dimensional overlay based on an overall planar topography between the indole/azaindole and C-7 substituents that had been deduced from structure-activity studies leading to the discovery of temsavir (3). 2-Substituted naphthalene- and quinoline-derived chemotypes emerged as the most interesting prototypes, with C-5 and C-6 substituents enhancing antiviral potency. Despite the fact that neither of these chemotypes incorporated a H-bond donor that has been shown to engage the side chain carboxylate of Asp113 in gp120, the antiviral potency of several analogues met or exceeded that of 3, demonstrating that engaging Asp113 is not a prerequisite for potent antiviral activity.
Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Indóis/farmacologia , Ligação Viral/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Indóis/síntese química , Indóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
We describe an efficient and convergent synthesis of a series of (1'S,2R,4'S)-3H-4'-azaspiro[benzo[4,5]imidazo[2,1-b]oxazole-2,2'-bicyclo[2.2.2]octanes] displaying potency for the α7 nicotinic acetylcholine receptor (nAChR) and good selectivity vs. the related 5-HT3A receptor.
Assuntos
Compostos Bicíclicos com Pontes/metabolismo , Desenho de Fármacos , Octanos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Conformação Molecular , Agonistas Nicotínicos/química , Agonistas Nicotínicos/metabolismo , Octanos/síntese química , Octanos/química , Ligação Proteica , Receptores 5-HT3 de Serotonina/química , Receptores 5-HT3 de Serotonina/metabolismo , Estereoisomerismo , Receptor Nicotínico de Acetilcolina alfa7/químicaRESUMO
The therapeutic treatment of negative symptoms and cognitive dysfunction associated with schizophrenia is a significant unmet medical need. Preclinical literature indicates that α7 neuronal nicotinic acetylcholine (nACh) receptor agonists may provide an effective approach to treating cognitive dysfunction in schizophrenia. We report herein the discovery and evaluation of 1c (BMS-933043), a novel and potent α7 nACh receptor partial agonist with high selectivity against other nicotinic acetylcholine receptor subtypes (>100-fold) and the 5-HT3A receptor (>300-fold). In vivo activity was demonstrated in a preclinical model of cognitive impairment, mouse novel object recognition. BMS-933043 has completed Phase I clinical trials.
RESUMO
Quinuclidine-containing spirooxazolines, as described in the previous report in this series, were demonstrated to have utility as α7 nicotinic acetylcholine receptor (α7 nAChR) partial agonists. In this work, the SAR of this chemotype was expanded to include an array of diazine heterocyclic substitutions. Many of the heterocyclic analogs were potent partial agonists of the α7 receptor, selective against other nicotinic receptors and the serotinergic 5HT3A receptor. (1'S,3'R,4'S)-N-(6-phenylpyrimidin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine, a potent and selective α7 nAChR partial agonist, was demonstrated to improve cognition in the mouse novel object recognition (NOR) model of episodic memory.
Assuntos
Desenho de Fármacos , Octanos/síntese química , Pirimidinas/síntese química , Compostos de Espiro/síntese química , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Cognição/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Estrutura Molecular , Octanos/química , Octanos/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
We describe the synthesis of quinuclidine-containing spiroimidates and their utility as α7 nicotinic acetylcholine receptor (nAChR) partial agonists. A convergent synthetic route allowed for rapid SAR investigation and provided a diverse set of fused 6,5-heteroaryl analogs. Two potent and selective α7 nAChR partial agonists, (1'S,3'R,4'S)-N-(7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine (20) and (1'S,3'R,4'S)-N-(7-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine (21), were identified. Both agonists improved cognition in a preclinical rodent model of learning and memory. Additionally, 5-HT3A receptor SAR suggested the presence of a steric site that when engaged led to significant loss of affinity at that receptor.
RESUMO
We describe the synthesis of quinuclidine-containing spiroguanidines and their utility as α7 neuronal nicotinic acetylcholine receptor (nAChR) partial agonists. The convergent synthetic route developed for this study allowed for rapid SAR investigation and provided access to a structurally diverse set of analogs. A potent and selective α7 nAChR partial agonist, N-(6-methyl-1,3-benzoxazol-2-yl)-3',5'-dihydro-4-azaspiro[bicyclo[2.2.2]octane-2,4'-imidazole]-2'-amine (BMS-910731, 16), was identified. This compound induced immediate early genes c-fos and Arc in a preclinical rodent model of α7 nAChR-derived cellular activation and plasticity. Importantly, the ability to incorporate selectivity for the α7 nACh receptor over the 5-HT3A receptor in this series suggested a significant difference in steric requirements between the two receptors.
Assuntos
Guanidina/farmacologia , Quinuclidinas/farmacologia , Compostos de Espiro/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Relação Dose-Resposta a Droga , Guanidina/análogos & derivados , Guanidina/química , Humanos , Estrutura Molecular , Quinuclidinas/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
The design and synthesis of a series of quinuclidine-containing spirooxazolidines ("spiroimidates") and their utility as α7 nicotinic acetylcholine receptor partial agonists are described. Selected members of the series demonstrated excellent selectivity for α7 over the highly homologous 5-HT3A receptor. Modification of the N-spiroimidate heterocycle substituent led to (1S,2R,4S)-N-isoquinolin-3-yl)-4'H-4-azaspiro[bicyclo[2.2.2]octane-2,5'oxazol]-2'-amine (BMS-902483), a potent α7 partial agonist, which improved cognition in preclinical rodent models.
Assuntos
Ciclo-Octanos/farmacologia , Desenho de Fármacos , Agonistas Nicotínicos/farmacologia , Compostos de Espiro/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Animais , Ciclo-Octanos/síntese química , Ciclo-Octanos/química , Relação Dose-Resposta a Droga , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Estrutura Molecular , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
The metabotropic glutamate receptor 5 (mGluR5) is an attractive target for the treatment of schizophrenia due to its role in regulating glutamatergic signaling in association with the N-methyl-d-aspartate receptor (NMDAR). We describe the synthesis of 1H-pyrazolo[3,4-b]pyridines and their utility as mGluR5 positive allosteric modulators (PAMs) without inherent agonist activity. A facile and convergent synthetic route provided access to a structurally diverse set of analogues that contain neither the aryl-acetylene-aryl nor aryl-methyleneoxy-aryl elements, the predominant structural motifs described in the literature. Binding studies suggest that members of our new chemotype do not engage the receptor at the MPEP and CPPHA mGluR5 allosteric sites. SAR studies culminated in the first non-MPEP site PAM, 1H-pyrazolo[3,4-b]pyridine 31 (BMT-145027), to improve cognition in a preclinical rodent model of learning and memory.
RESUMO
As part of the SAR profiling of the indole-oxoacetic piperazinyl benzamide class of HIV-1 attachment inhibitors, substitution at the C7 position of the lead 4-fluoroindole 2 with various 5- and 6-membered heteroaryl moieties was explored. Highly potent (picomolar) inhibitors of pseudotyped HIV-1 in a primary, cell-based assay were identified and select examples were shown to possess nanomolar inhibitory activity against M- and T-tropic viruses in cell culture. These C7-heteroaryl-indole analogs maintained the ligand efficiency (LE) of 2 and were also lipophilic efficient as measured by LLE and LELP. Pharmacokinetic studies of this class of inhibitor in rats showed that several possessed substantially improved IV clearance and half-lives compared to 2. Oral exposure in the rat correlated with membrane permeability as measured in a Caco-2 assay where the highly permeable 1,2,4-oxadiazole analog 13 exhibited the highest exposure.
Assuntos
Fármacos Anti-HIV/química , HIV-1/metabolismo , Indóis/química , Administração Oral , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Meia-Vida , Humanos , Indóis/síntese química , Indóis/farmacocinética , Microssomos Hepáticos/metabolismo , Ratos , Relação Estrutura-Atividade , Ligação Viral/efeitos dos fármacosRESUMO
A series of substituted carboxamides at the indole C7 position of the previously described 4-fluoro-substituted indole HIV-1 attachment inhibitor 1 was synthesized and the SAR delineated. Heteroaryl carboxamide inhibitors that exhibited pM potency in the primary cell-based assay against a pseudotype virus expressing a JRFL envelope were identified. The simple methyl amide analog 4 displayed a promising in vitro profile, with its favorable HLM stability and membrane permeability translating into favorable pharmacokinetic properties in preclinical species.
Assuntos
Amidas/química , Fármacos Anti-HIV/química , HIV-1/metabolismo , Indóis/química , Amidas/síntese química , Amidas/farmacocinética , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cristalografia por Raios X , Cães , HIV-1/efeitos dos fármacos , Meia-Vida , Haplorrinos , Humanos , Microssomos Hepáticos/metabolismo , Conformação Molecular , Ratos , Relação Estrutura-Atividade , Ligação Viral/efeitos dos fármacosRESUMO
The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore.
Assuntos
Inibidores da Fusão de HIV/química , Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , Indóis/farmacologia , Ligação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Cães , Proteína gp120 do Envelope de HIV/metabolismo , Infecções por HIV/prevenção & controle , Humanos , Indóis/química , Indóis/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.
Assuntos
Fármacos Anti-HIV/farmacologia , Antígenos CD4/metabolismo , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/metabolismo , Indóis/farmacologia , Piperazinas/farmacologia , Administração Oral , Animais , Fármacos Anti-HIV/farmacocinética , Disponibilidade Biológica , Antagonistas dos Receptores CCR5 , Cães , Humanos , Indóis/química , Indóis/farmacocinética , Infusões Intravenosas , Macaca fascicularis , Piperazinas/química , Piperazinas/farmacocinética , Ratos , Receptores CXCR4/antagonistas & inibidoresRESUMO
A stereoselective radical cascade cyclization to 5alpha-pregnanes is presented. Oxidative free radical cyclization of an appropriately substituted chloro cyano ester polyene was used to introduce the all trans stereochemistry in the steroid nucleus. The cyano group was utilized to introduce a C-8beta angular hydrogen, while the chloro ester moiety served as an entry to the geminal hydrogens at C-4.