RESUMO
The evolution of gamma-secretase modulators (GSMs) through the introduction of novel heterocycles with the goal of aligning activity for reducing the levels of Aß42 and properties consistent with a drug-like molecule are described. The insertion of a methoxypyridine motif within the tetracyclic scaffold provided compounds with improved activity for arresting Aß42 production as well as improved properties, including solubility. In vivo pharmacokinetic analysis demonstrated that several compounds within the novel series were capable of crossing the BBB and accessing the therapeutic target. Treatment with methoxypyridine-derived compound 64 reduced Aß42 levels in the plasma of J20 mice, in addition to reducing Aß42 levels in the plasma and brain of Tg2576 mice.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Piridinas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/análise , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. We describe herein further structure-activity relationship exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).
Assuntos
Benzamidas/química , Benzamidas/farmacologia , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Glicina/líquido cefalorraquidiano , Glicina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Macaca fascicularis , Masculino , Metilação , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The design and construction of a series of novel aminothiazole-derived γ-secretase modulators is described. The incorporation of heterocyclic replacements of the terminal phenyl D-ring of lead compound 1 was conducted in order to align potency with favorable drug-like properties. γ-Secretase modulator 28 displayed good activity for in vitro inhibition of Aß42, as well as substantial improvement in ADME and physicochemical properties, including aqueous solubility. Pharmacokinetic evaluation of compound 28 in mice revealed good brain penetration, as well as good clearance, half-life, and volume of distribution which collectively support the continued development of this class of compounds.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Desenho de Fármacos , Tiazóis/química , Secretases da Proteína Precursora do Amiloide/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Meia-Vida , Humanos , Cinética , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Ratos , Solubilidade , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinéticaRESUMO
The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
Assuntos
Inibidores Enzimáticos/farmacologia , Iminas/farmacologia , Pirimidinonas/farmacologia , Renina/antagonistas & inibidores , Administração Oral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Iminas/síntese química , Iminas/química , Modelos Moleculares , Estrutura Molecular , Pirimidinonas/síntese química , Pirimidinonas/química , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Na(v)1.7 inhibitory activity and moderate selectivity over Na(v)1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 µM.
Assuntos
Analgésicos/farmacologia , Gânglios Espinais/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.7/química , Neuralgia/tratamento farmacológico , Bloqueadores dos Canais de Sódio/farmacologia , Nervos Espinhais/efeitos dos fármacos , Compostos de Espiro/farmacologia , Analgésicos/química , Animais , Estrutura Molecular , Técnicas de Patch-Clamp , Quinoxalinas/química , Ratos , Bloqueadores dos Canais de Sódio/química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.
Assuntos
Antifúngicos/química , Inibidores Enzimáticos/química , Glucosiltransferases/antagonistas & inibidores , Piridazinas/química , Sulfonamidas/química , Animais , Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Glucosiltransferases/metabolismo , Meia-Vida , Camundongos , Testes de Sensibilidade Microbiana , Piridazinas/farmacocinética , Piridazinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêuticoRESUMO
A total synthesis of the racemic natural product tylophorine [(+/-)-1] has been demonstrated using the palladium-catalyzed carboamination method developed by Wolfe and co-workers. In this case, an electron-rich aryl bromide 18 was prepared in four steps and subjected to palladium-catalyzed Wolfe carboamination conditions with olefinic carbamate 7 to provide the racemic 2-(arylmethyl)pyrrolidine (+/-)-19 in good yield and was further elaborated to racemic tylophorine. This application of the Wolfe carboamination protocol as a key step to construct a natural product provides further evidence of the utility of the method.
Assuntos
Alcaloides/síntese química , Antineoplásicos Fitogênicos/síntese química , Carbamatos/química , Indolizinas/síntese química , Paládio/química , Fenantrenos/síntese química , Alcaloides/química , Alcenos/química , Aminação , Antineoplásicos Fitogênicos/química , Catálise , Hidrocarbonetos Bromados/química , Hidrocarbonetos Cíclicos/química , Indolizinas/química , Modelos Químicos , Fenantrenos/química , Pirrolidinas/química , EstereoisomerismoRESUMO
The title compounds, bis(ammonium) naphthalene-1,5-disulfonate, 2NH(4)(+).C(10)H(6)O(6)S(2)(2-), and bis[1-(hydroxymethyl)-3,5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane] 1,5-naphthalenedisulfonate, 2C(7)H(15)N(4)O(+).C(10)H(6)O(6)S(2)(2-), were prepared from the acid-promoted reaction of hexamethylenetetramine. In both structures, the disulfonate anion is positioned on an inversion center, with each sulfonate group contributing to the supramolecular assemblies via hydrogen bonds. The ammonium cations are linked to sulfonate groups by four distinct N(+)-H.(-)O-S contacts [N.O = 2.846 (2)-2.898 (2) A and N-H.O = 160 (2)-175 (2) degrees ], whereas the 1-(hydroxymethyl)-3,5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane cations form one O-H.(-)O-S [O.O = 2.628 (2) A and O-H.O = 176 degrees ] and three C-H.(-)O-S [C.O = 3.359 (2)-3.380 (2) A and C-H.O = 148-155 degrees ] interactions to neighboring sulfonate groups.