RESUMO
Therapeutic reactivation of the γ-globin genes for fetal hemoglobin (HbF) production is an attractive strategy for treating ß-thalassemia and sickle cell disease. It was reported that genetic knockdown of the histone lysine methyltransferase EHMT2/1 (G9a/GLP) is sufficient to induce HbF production. The aim of the present work was to acquire a G9a/GLP inhibitor that induces HbF production sufficiently. It was revealed that tetrahydroazepine has versatility as a side chain in various skeletons. We ultimately obtained a promising aminoindole derivative (DS79932728), a potent and orally bioavailable G9a/GLP inhibitor that was found to induce γ-globin production in a phlebotomized cynomolgus monkey model. This work could facilitate the development of effective new approaches for treating ß-thalassemia and sickle cell disease.
RESUMO
Inducing oligodendrocyte progenitor cell (OPC) differentiation is a novel therapeutic strategy for the treatment of demyelinating diseases such as multiple sclerosis (MS). In the preceding article, we detailed the discovery of compound 1, a potent inducer of OPC differentiation possessing a characteristic spiroindoline structure. Also, we found that N-methylation and des-carbonyl compound 1 (4) led to a loss in potency. Herein, we describe our investigations of a conformation-based hypothesis for OPC differentiation activity based on the preferred conformation of the spiro core, and further structure-activity relationship (SAR) exploration led to the identification of 6-CF3 derivative 8, which was more potent compared to compound 1.
Assuntos
Desenho de Fármacos , Indóis/farmacologia , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Compostos de Espiro/farmacologia , Animais , Diferenciação Celular , Relação Dose-Resposta a Droga , Indóis/síntese química , Indóis/química , Estrutura Molecular , Ratos , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
A novel series of spiroindoline derivatives was discovered for use as inducers of oligodendrocyte progenitor cell (OPC) differentiation, resulting from optimization of screening hit 1. Exploration of structure-activity relationships led to compound 18, which showed improved potency (rOPC EC50 = 0.0032 µM). Furthermore, oral administration of compound 18 significantly decreased clinical severity in an experimental autoimmune encephalomyelitis (EAE) model.
Assuntos
Descoberta de Drogas , Encefalomielite Autoimune Experimental/tratamento farmacológico , Indóis/farmacologia , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Compostos de Espiro/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Encefalomielite Autoimune Experimental/patologia , Feminino , Indóis/síntese química , Indóis/química , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ratos , Ratos Wistar , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
Our aim was to examine the effects of ASB17061, an orally active novel chymase inhibitor, on angiotensin II-induced abdominal aortic aneurysm (AAA) in apolipoprotein E-deficient mice. Oral administration of ASB17061 (10 mg/kg) significantly suppressed angiotensin II-induced AAA formation in these mice. The pro-matrix metalloproteinase-9 (pro-MMP-9) level in AAA lesions was significantly suppressed by ASB17061 treatment, indicating that ASB17061 inhibited the accumulation of pro-MMP-9-producing cells in AAA lesions. Mouse mast cell protease 4 (mMCP-4, human chymase ortholog) was injected into BALB/c mice intraperitoneally to examine the ability of mMCP-4 to induce the accumulation of pro-MMP-9-producing cells. An intraperitoneal injection of mMCP-4 induced the accumulation of pro-MMP-9-producing cells including CD11b + Gr-1 + cells. Taken together, these data indicate that ASB17061 is a promising novel oral therapeutic agent for human AAA.
Assuntos
Angiotensina II/farmacologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/prevenção & controle , Apolipoproteínas E/deficiência , Ácido Benzoico/farmacologia , Quimases/antagonistas & inibidores , Inibidores de Serina Proteinase/farmacologia , Animais , Aneurisma da Aorta Abdominal/metabolismo , Colite/prevenção & controle , Precursores Enzimáticos/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB CRESUMO
A series of imidazolinylindole derivatives were discovered as novel kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Structure-activity relationship (SAR) studies led to the identification of potent human KLK7 inhibitors. By further modification of the benzenesulfonyl moiety to overcome species differences in inhibitory activity, potent inhibitors against both human and mouse KLK7 were identified. Furthermore, the complex structure of 25 with mouse KLK7 could explain the SAR and the cause of the species differences in inhibitory activity.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Imidazolinas/farmacologia , Indóis/farmacologia , Calicreínas/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Imidazolinas/síntese química , Imidazolinas/química , Indóis/síntese química , Indóis/química , Calicreínas/metabolismo , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of compounds was discovered that induce the production of VGF mRNA in SH-SY5Y cells and exhibit cytoprotection under tunicamycin induced endoplasmic reticulum (ER) stress. The aminophenol ring and linker chain of the template SUN N8075 (1) was modified to yield compounds with higher efficacy and lower propensity for adverse effects.
Assuntos
Fatores de Crescimento Neural/biossíntese , Piperazinas/farmacologia , Linhagem Celular Tumoral , Citoproteção , Relação Dose-Resposta a Droga , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , RNA Mensageiro/biossíntese , Relação Estrutura-Atividade , Tunicamicina/farmacologiaRESUMO
A series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were prepared as kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Previously reported compounds 1-3 were potent human KLK7 inhibitors; however, they did not exhibit inhibitory activity against mouse KLK7. Comparison of the human and mouse KLK7 structures reveals the cause of this species differences; therefore, compounds that could inhibit both KLK7s were designed, synthesized, and evaluated. Through this structure-based drug design, compound 22g was identified as an inhibitor against human and mouse KLK7, and only one of the enantiomers, (-)-22g, exhibited potent inhibitory activity. Furthermore, the crystal structure of mouse KLK7 complexed with 22g enabled the elucidation of structure-activity relationships and justified 22g as a valuable compound to overcome the species differences.
Assuntos
Azepinas/química , Calicreínas/metabolismo , Inibidores de Proteases/síntese química , Sequência de Aminoácidos , Animais , Azepinas/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Calicreínas/antagonistas & inibidores , Camundongos , Inibidores de Proteases/metabolismo , Estrutura Terciária de Proteína , Alinhamento de Sequência , Especificidade da Espécie , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were investigated as human kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Based on the X-ray co-crystal structure of compound 1 bound to human KLK7, the derivatives of this scaffold were designed, synthesized, and evaluated. Through structure-activity relationship studies focused on the side chain located in the prime site region of the enzyme, representative compounds 15, 33a, and 35a were identified as highly potent and selective inhibitors of human KLK7.
Assuntos
Azepinas/farmacologia , Calicreínas/antagonistas & inibidores , Azepinas/síntese química , Azepinas/química , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Calicreínas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Based on insight from the X-ray crystal structure of human chymase in complex with compound 1, a lactam carbonyl of the diazepane core was exchanged with O-substituted oxyimino group, leading to amidoxime derivatives. This modification resulted in highly potent chymase inhibitors, such as O-phenylamidoxime 5f. X-ray crystal structure analysis indicated that compound 5f induced movement of the Leu99 and Tyr94 side chains at the S2 site, and the increase in inhibitory activity of O-phenyl amidoxime derivatives suggested that the O-phenyl moiety interacted with the Tyr94 residue. Surface plasmon resonance experiments showed that compound 5f had slower association and dissociation kinetics and the calculated residence time of compound 5f to human chymase was extended compared to that of amide compound 1.
Assuntos
Quimases/antagonistas & inibidores , Desenho de Fármacos , Oximas/farmacologia , Inibidores de Serina Proteinase/farmacologia , Sítios de Ligação/efeitos dos fármacos , Quimases/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Oximas/síntese química , Oximas/química , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Relação Estrutura-AtividadeRESUMO
Compound 1, composed of a 1,3,6-trisubstituted 1,4-diazepane-7-one, was discovered as a novel human kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme, SCCE) inhibitor, and its derivatives were synthesized and evaluated. Structure-activity relationship studies of the amidoxime unit and benzoic acid part of this new scaffold led to the identification of 25 and 34, which were more potent than the hit compound, 1. The X-ray co-crystal structure of compound 25 and human KLK7 revealed the characteristic interactions and enabled explanations of the structure-activity relationship.
Assuntos
Azepinas/farmacologia , Descoberta de Drogas , Calicreínas/antagonistas & inibidores , Inibidores de Serina Proteinase/farmacologia , Azepinas/síntese química , Azepinas/química , Relação Dose-Resposta a Droga , Humanos , Calicreínas/metabolismo , Estrutura Molecular , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Relação Estrutura-AtividadeRESUMO
We report on the use of microcrystallization in capillaries to fabricate patterned crystalline microstructures of the low-bandgap ambipolar quinoidal quaterthiophene derivative (QQT(CN)4) from a chloroform solution. Aligned needle-shaped QQT(CN)4 crystals were formed in thin film microstructures using either open- or closed- capillaries made of polydimethylsiloxane (PDMS). Their charge transport properties were evaluated in a bottom-gate top-contact transistor configuration. Hole and electron mobilities were found to be as high as 0.17 and 0.083 cm(2) V(-1) s(-1), respectively, approaching the values previously obtained in individual QQT(CN)4 single crystal microneedles. It was possible to control the size of the needle crystals and the microline arrays by adjusting the structure of the PDMS mold and the concentration of QQT(CN)4 solution. These results demonstrate that the microcrystallization in capillaries technique can be used to simultaneously pattern organic needle single crystals and control the microcrystallization processes. Such a simple and versatile method should be promising for the future development of high-performance organic electronic devices.
RESUMO
Structural optimization of 2-aminonicotinamide derivatives as ghrelin receptor inverse agonists is reported. So as to avoid mechanism-based inactivation (MBI) of CYP3A4, 1,3-benzodioxol ring of the lead compound was modified. Improvement of the main activity and lipophilicity was achieved simultaneously, leading to compound 18a, which showed high lipophilic ligand efficiency (LLE) and low MBI activity.
Assuntos
6-Aminonicotinamida/análogos & derivados , 6-Aminonicotinamida/farmacologia , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Citocromo P-450 CYP3A/metabolismo , Agonismo Inverso de Drogas , Receptores de Grelina/agonistas , 6-Aminonicotinamida/metabolismo , Fármacos Antiobesidade/metabolismo , Descoberta de Drogas , Humanos , Microssomos Hepáticos/metabolismo , Obesidade/tratamento farmacológico , Receptores de Grelina/metabolismoRESUMO
A series of 2-alkylamino nicotinamide analogs was prepared as orally active ghrelin receptor (ghrelinR) inverse agonists. Starting from compound 1, oral bioavailability was improved by modifying metabolically unstable sites and reducing molecular weight. Brain-permeable compound 33 and compound 24 with low brain permeability were tested in rat models of obesity; 30 mg/kg of compound 33 suppressed weight gain. PK/PD analysis revealed that the anti-obesity effect of ghrelinR inverse agonists depends on their brain concentrations.
Assuntos
Fármacos Antiobesidade/química , Receptores de Grelina/agonistas , Administração Oral , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/farmacocinética , Modelos Animais de Doenças , Agonismo Inverso de Drogas , Meia-Vida , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microssomos Hepáticos/metabolismo , Niacinamida/administração & dosagem , Niacinamida/química , Niacinamida/farmacocinética , Obesidade/tratamento farmacológico , Obesidade/patologia , Ratos , Ratos Sprague-Dawley , Receptores de Grelina/metabolismo , Relação Estrutura-AtividadeRESUMO
New inverse agonists of the ghrelin receptor (ghrelinR) were obtained through high-throughput screening and subsequent structural modification of 2-aminoalkyl nicotinamide derivatives. The key structural feature to improve in vitro activity was the introduction of a diazabicyclo ring at the 5-position of the pyridine ring. The final product showed potent inverse agonist activity and, despite its low brain permeability, reduced food intake in both normal and obese mice. These results implied that peripheral ghrelinR activity is important for appetite control and that a peripheral ghrelinR inverse agonist could be an anti-obesity drug with reduced risk of central nervous system (CNS)-related side effects.
Assuntos
Niacinamida/análogos & derivados , Receptores de Grelina/agonistas , Receptores de Grelina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Regulação do Apetite/efeitos dos fármacos , Desenho de Fármacos , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Niacinamida/química , Niacinamida/farmacologia , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia , Ratos , Relação Estrutura-AtividadeRESUMO
High-performance non-volatile memory that can operate under various mechanical deformations such as bending and folding is in great demand for the future smart wearable and foldable electronics. Here we demonstrate non-volatile solution-processed ferroelectric organic field-effect transistor memories operating in p- and n-type dual mode, with excellent mechanical flexibility. Our devices contain a ferroelectric poly(vinylidene fluoride-co-trifluoroethylene) thin insulator layer and use a quinoidal oligothiophene derivative (QQT(CN)4) as organic semiconductor. Our dual-mode field-effect devices are highly reliable with data retention and endurance of >6,000 s and 100 cycles, respectively, even after 1,000 bending cycles at both extreme bending radii as low as 500 µm and with sharp folding involving inelastic deformation of the device. Nano-indentation and nano scratch studies are performed to characterize the mechanical properties of organic layers and understand the crucial role played by QQT(CN)4 on the mechanical flexibility of our devices.
RESUMO
A novel series of 6-benzyl substituted 4-aminocarbonyl-1,4-diazepane-2,5-diones were explored as human chymase inhibitors using structure-based drug design according to the X-ray cocrystal structure of chymase and compound 1. The optimization focused on the prime site led to the attainment of compounds that showed potent inhibitory activity, and among them, 18R shows a novel interaction mode.
Assuntos
Azepinas/síntese química , Quimases/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/química , Etilmorfina/síntese química , Azepinas/química , Azepinas/farmacologia , Domínio Catalítico , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Etilmorfina/química , Etilmorfina/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A chymase inhibitor SUN13834 has been shown to improve skin condition in animal models for atopic dermatitis. In the present study, effective dosages of SUN13834 for atopic dermatitis patients were predicted by pharmacokinetic/pharmacodynamic (PK/PD) analyses of SUN13834 in NC/Nga mice, which spontaneously develop atopic dermatitis-like skin lesions. For the PK/PD analyses, we utilized the minimum effective plasma concentration of unbound SUN13834 in late-phase reaction of trinitrochlorobenzene (TNCB)-induced biphasic dermatitis in mice, based on the assumption that the minimum effective plasma concentrations are the same among the two animal models. In late-phase reaction of biphasic dermatitis, SUN13834 was most effective when its plasma concentration was highest at the elicitation, and the minimum effective plasma concentration of unbound SUN13834 at the elicitation was calculated to be 0.13-0.2 ng/mL. Oral administration of SUN13834 improved dermatitis in NC/Nga mice at 15 mg/kg (twice a day; bid) and 30 mg/kg (once a day; qd), but not at 60 mg/kg (every other day; eod). At the three dosages, the duration times over the plasma level of 0.13-0.2 ng/mL were 16.1-20.3, 10.7-12.2 and 7.8-8.8h, respectively, suggesting an importance of maintenance of the minimum effective plasma concentration for at least about 10-12h. The clinical effective dosage predicted in this paper is also discussed in relation to a recently conducted Phase 2a study.
Assuntos
Azepinas/administração & dosagem , Quimases/metabolismo , Dermatite Atópica/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Pele/efeitos dos fármacos , Administração Oral , Animais , Azepinas/farmacocinética , Ensaios Clínicos Fase II como Assunto , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/enzimologia , Suscetibilidade a Doenças , Cálculos da Dosagem de Medicamento , Inibidores Enzimáticos/farmacocinética , Humanos , Camundongos , Camundongos Endogâmicos , Cloreto de Picrila/administração & dosagem , Pele/patologiaRESUMO
We observed the temporal development of surface waves and investigated their power propagation loss in typical photorefractive polymer films sandwiched between ITO glass substrates. We found that amplified scattered waves generated in a pumped region started to develop into surface waves from a point where they reached the substrate through the self-bending effect. The surface waves propagated over a distance of 1.7 mm, thereby confining the power to a region at a distance of 30 microns from the substrate. Considerable propagation power loss of the surface waves was observed at a low pumping power of the beam; however, the power loss decreased considerably when the beam had high power.