RESUMO
The c-MYC oncogene transcription factor has been implicated in cell cycle regulation controlling cell growth and proliferation. It is tightly regulated in normal cells, but has been shown to be deregulated in cancer cells, and is thus an attractive target for oncogenic therapies. Building upon previous SAR, a series of analogues containing benzimidazole core replacements were prepared and evaluated, leading to the identification of imidazopyridazine compounds that were shown to possess equivalent or improved c-MYC HTRF pEC50 values, lipophilicity, solubility, and rat pharmacokinetics. The imidazopyridazine core was therefore determined to be superior to the original benzimidazole core and a viable alternate for continued lead optimization and medicinal chemistry campaigns.
Assuntos
Aminopiridinas , Proteínas Proto-Oncogênicas c-myc , Ratos , Animais , Proteínas Proto-Oncogênicas c-myc/metabolismo , Regulação da Expressão Gênica , Fatores de Transcrição/metabolismo , BenzimidazóisRESUMO
A series of methoxynaphthalene amides were prepared and evaluated as alternatives to quinolizidinone amide M1 positive allosteric modulators. A methoxy group was optimal for M1 activity and addressed key P-gp issues present in the aforementioned quinolizidinone amide series.
Assuntos
Amidas/química , Naftalenos/química , Quinolizidinas/química , Receptor Muscarínico M1/metabolismo , Regulação Alostérica , Amidas/síntese química , Amidas/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Camundongos , Ligação Proteica , Receptor Muscarínico M1/química , Relação Estrutura-AtividadeRESUMO
Analogs of the dual orexin receptor antagonist filorexant were prepared. Replacement of the ether linkage proved highly sensitive toward modification with an acetylene linkage providing compounds with the best in vitro and in vivo potency profiles.
Assuntos
Acetileno/química , Antagonistas dos Receptores de Orexina , Piperidinas/farmacologia , Pirimidinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Camundongos , Camundongos Knockout , Estrutura Molecular , Receptores de Orexina/deficiência , Receptores de Orexina/metabolismo , Piperidinas/síntese química , Piperidinas/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
E1A binding protein (p300) and CREB binding protein (CBP) are two highly homologous and multidomain histone acetyltransferases. These two proteins are involved in many cellular processes by acting as coactivators of a large number of transcription factors. Dysregulation of p300/CBP has been found in a variety of cancers and other diseases, and inhibition has been shown to decrease Myc expression. Herein, we report the identification of a series of highly potent, proline-based small-molecule p300/CBP histone acetyltransferase (HAT) inhibitors using DNA-encoded library technology in combination with high-throughput screening. The strategy of reducing ChromlogD and fluorination of metabolic soft spots was explored to improve the pharmacokinetic properties of potent p300 inhibitors. Fluorination of both cyclobutyl and proline rings of 22 led to not only reduced clearance but also improved cMyc cellular potency.
Assuntos
Proteína de Ligação a CREB , Ensaios de Triagem em Larga Escala , Prolina , Histona Acetiltransferases , Proteínas E1A de Adenovirus/metabolismo , Fatores de Transcrição de p300-CBP , DNA , TecnologiaRESUMO
SAR study of the piperidine moiety in a series of quinolizidinone carboxylic acid M(1) positive allosteric modulators was examined. While the SAR was generally flat, compounds were identified with high CNS exposure to warrant additional in vivo evaluation.
Assuntos
Piperidinas/farmacologia , Regulação Alostérica , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Piperidinas/metabolismo , Relação Estrutura-AtividadeRESUMO
Fused aromatics such as naphthalene were identified as highly potent and CNS penetrant M(1) positive allosteric modulators during an SAR study to replace the phenyl B-ring linkage.
Assuntos
Naftóis/química , Receptor Muscarínico M1/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/sangue , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/líquido cefalorraquidiano , Regulação Alostérica/efeitos dos fármacos , Animais , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Humanos , Estrutura Molecular , Naftóis/farmacologia , Quinolonas/química , Quinolonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A series of benzothiophene methyl amines were examined in an effort to identify non-amidine chemotypes with reduced polypharmacology from existing leads with the goal of finding potent ASIC3 channel blockers to advance the therapeutic evaluation of ASIC3 inhibition.
Assuntos
Proteínas do Tecido Nervoso/antagonistas & inibidores , Bloqueadores dos Canais de Sódio/química , Canais Iônicos Sensíveis a Ácido , Amidinas/química , Amilorida/química , Animais , Proteínas do Tecido Nervoso/metabolismo , Ratos , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/metabolismo , Relação Estrutura-AtividadeRESUMO
Elevated expression of the c-MYC oncogene is one of the most common abnormalities in human cancers. Unfortunately, efforts to identify pharmacological inhibitors that directly target MYC have not yet yielded a drug-like molecule due to the lack of any known small molecule binding pocket in the protein, which could be exploited to disrupt MYC function. We have recently described a strategy to target MYC indirectly, where a screening effort designed to identify compounds that can rapidly decrease endogenous c-MYC protein levels in a MYC-amplified cell line led to the discovery of a compound series that phenocopies c-MYC knockdown by siRNA. Herein, we describe our medicinal chemistry program that led to the discovery of potent, orally bioavailable c-MYC-reducing compounds. The development of a minimum pharmacophore model based on empirical structure activity relationship as well as the property-based approach used to modulate pharmacokinetics properties will be highlighted.
Assuntos
Descoberta de Drogas , Proteínas Proto-Oncogênicas c-myc/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Área Sob a Curva , Linhagem Celular Tumoral , Meia-Vida , Humanos , Proteínas Proto-Oncogênicas c-myc/genética , Ratos , Bibliotecas de Moléculas Pequenas/farmacocinética , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The phenyl ring in a series of quinolone carboxylic acid M(1) positive allosteric modulators was replaced with a variety of heterocycles in order to reduce protein plasma binding and enhance CNS exposure.
Assuntos
Ácidos Carboxílicos/farmacologia , Compostos Heterocíclicos/farmacologia , Piridonas/química , Regulação Alostérica , Animais , Proteínas Sanguíneas/química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Humanos , RatosRESUMO
Incorporation of pyridines and diazines into the biphenyl region of quinolone carboxylic acid derived M(1) positive allosteric modulators was investigated as a means of lowering plasma protein binding to enhance CNS exposure.
Assuntos
Proteínas Sanguíneas/química , Piridinas/química , Receptor Muscarínico M1/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Regulação Alostérica , Animais , Proteínas Sanguíneas/metabolismo , Humanos , Ligação Proteica , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Receptor Muscarínico M1/metabolismo , Relação Estrutura-AtividadeRESUMO
Replacement of a phenyl ring with N-linked heterocycles in a series of quinolone carboxylic acid M1 positive allosteric modulators was investigated. In particular, a pyrazole derivative exhibited improvements in potency, free fraction, and CNS exposure.
Assuntos
Ácidos Carboxílicos/síntese química , Compostos Heterocíclicos/síntese química , Pirazóis/síntese química , Quinolinas/síntese química , Regulação Alostérica , Animais , Células CHO , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Linhagem Celular , Cricetinae , Cricetulus , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A series of amiloride derivatives modified at the 5-position of the pyrazine ring were evaluated as inhibitors of acid-sensing ion channel-3 (ASIC3), a novel target for the treatment of chronic pain.
Assuntos
Amilorida/análogos & derivados , Química Farmacêutica/métodos , Proteínas do Tecido Nervoso/química , Dor/tratamento farmacológico , Canais de Sódio/química , Canais Iônicos Sensíveis a Ácido , Acidose , Amilorida/química , Aminas/química , Animais , Desenho de Fármacos , Eletrofisiologia , Concentração Inibidora 50 , Masculino , Modelos Químicos , Pirazinas/química , Ratos , Ratos Sprague-DawleyRESUMO
A series of indole amidines modified at the 2-position of the indole ring were evaluated as inhibitors of Acid-Sensing Ion Channel-3 (ASIC3), a novel target for the treatment of chronic pain.
Assuntos
Amidinas/química , Química Farmacêutica/métodos , Canais de Sódio/química , Canais Iônicos Sensíveis a Ácido , Animais , Desenho de Fármacos , Eletrofisiologia , Indóis/química , Concentração Inibidora 50 , Canais Iônicos/química , Masculino , Modelos Químicos , Naproxeno/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
After oral treatment (once daily) for 4 weeks with the potent bradykinin B(1) receptor antagonist methyl 3-chloro-3'-fluoro-4'-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)-amino]ethyl}-1,1'-biphenyl-2-carboxylate (MK-0686), rhesus monkeys (Macaca mulatta) exhibited significantly reduced systemic exposure of the compound in a dose-dependent manner, suggesting an occurrence of autoinduction of MK-0686 metabolism. This possibility is supported by two observations. 1) MK-0686 was primarily eliminated via biotransformation in rhesus monkeys, with oxidation on the chlorophenyl ring as one of the major metabolic pathways. This reaction led to appreciable formation of a dihydrodiol (M11) and a hydroxyl (M13) product in rhesus liver microsomes supplemented with NADPH. 2) The formation rate of these two metabolites determined in liver microsomes from MK-0686-treated groups was > or = 2-fold greater than the value for a control group. Studies with recombinant rhesus P450s and monoclonal antibodies against human P450 enzymes suggested that CYP2C75 played an important role in the formation of M11 and M13. The induction of this enzyme by MK-0686 was further confirmed by a concentration-dependent increase of its mRNA in rhesus hepatocytes, and, more convincingly, the enhanced CYP2C proteins and catalytic activities toward CYP2C75 probe substrates in liver microsomes from MK-0686-treated animals. Furthermore, a good correlation was observed between the rates of M11 and M13 formation and hydroxylase activities toward probe substrates determined in a panel of liver microsomal preparations from control and MK-0686-treated animals. Therefore, MK-0686, both a substrate and inducer for CYP2C75, caused autoinduction of its own metabolism in rhesus monkeys by increasing the expression of this enzyme.
Assuntos
Acetamidas/farmacocinética , Benzoatos/farmacocinética , Antagonistas de Receptor B1 da Bradicinina , Sistema Enzimático do Citocromo P-450/metabolismo , Acetamidas/sangue , Acetamidas/urina , Animais , Benzoatos/sangue , Benzoatos/urina , Bile/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Sistema Enzimático do Citocromo P-450/genética , Feminino , Hepatócitos/metabolismo , Humanos , Macaca mulatta , Masculino , Microssomos Hepáticos/metabolismo , Receptor de Pregnano X , Receptor B1 da Bradicinina/metabolismo , Receptores de Esteroides/metabolismo , Proteínas Recombinantes/metabolismoRESUMO
The design and synthesis of a novel class of human bradykinin B1 antagonists featuring difluoroethyl ether and isoxazole carboxamide moieties are disclosed. Compound 7g displayed excellent pharmacokinetic properties, efficient ex vivo receptor occupancy, and low potential for P450 induction via PXR activation.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Isoxazóis/farmacologia , Receptores de Esteroides/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Cães , Humanos , Isoxazóis/farmacocinética , Macaca mulatta , Receptor de Pregnano X , Ratos , Ratos Sprague-DawleyRESUMO
A series of carbo- and heterocyclic alpha-hydroxy amide-derived bradykinin B1 antagonists was prepared and evaluated. A 4,4-difluorocyclohexyl alpha-hydroxy amide was incorporated along with a 2-methyl tetrazole in lieu of an oxadiazole to afford a suitable compound with good pharmacokinetic properties, CNS penetration, and clearance by multiple metabolic pathways.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Tetrazóis/síntese química , Tetrazóis/farmacologia , Amidas/química , Amidas/farmacocinética , Animais , Sistema Nervoso Central/efeitos dos fármacos , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacocinéticaRESUMO
Antagonism of the bradykinin B(1) receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating alpha-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B(1) receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure.
Assuntos
Amidas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Amidas/química , Amidas/farmacocinética , Animais , Disponibilidade Biológica , Barreira Hematoencefálica , Inibidores das Enzimas do Citocromo P-450 , Cães , Meia-Vida , Humanos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Identification of ligands that selectively activate the M1 muscarinic signaling pathway has been sought for decades to treat a range of neurological and cognitive disorders. Herein, we describe the optimization efforts focused on addressing key physicochemical and safety properties, ultimately leading to the clinical candidate MK-7622, a highly selective positive allosteric modulator of the M1 muscarinic receptor that has entered Phase II studies in patients with Alzheimer's disease.
RESUMO
A series of biphenylaminocyclopropane carboxamide based bradykinin B1 receptor antagonists has been developed that possesses good pharmacokinetic properties and is CNS penetrant. Discovery that the replacement of the trifluoropropionamide in the lead structure with polyhaloacetamides, particularly a trifluoroacetamide, significantly reduced P-glycoprotein mediated efflux for the series proved essential. One of these novel bradykinin B1 antagonists (13b) also exhibited suitable pharmacokinetic properties and efficient ex vivo receptor occupancy for further development as a novel approach for the treatment of pain and inflammation.
Assuntos
Acetamidas/síntese química , Amidas/síntese química , Compostos de Aminobifenil/síntese química , Benzoatos/síntese química , Antagonistas de Receptor B1 da Bradicinina , Encéfalo/metabolismo , Ciclopropanos/síntese química , Medula Espinal/metabolismo , Acetamidas/farmacocinética , Acetamidas/farmacologia , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Compostos de Aminobifenil/farmacocinética , Compostos de Aminobifenil/farmacologia , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Benzoatos/farmacocinética , Benzoatos/farmacologia , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Células CHO , Chlorocebus aethiops , Cricetinae , Cricetulus , Ciclopropanos/farmacocinética , Ciclopropanos/farmacologia , Feminino , Humanos , Macaca mulatta , Masculino , Camundongos , Coelhos , Ensaio Radioligante , Ratos , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
Developing new antiretroviral therapies for HIV-1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethylâ (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand-transfer inhibitor approved for the treatment of HIV infection with twice-daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK-8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug-drug interaction profile of raltegravir.