RESUMO
A series of conformationally restricted homotryptamines has been synthesized and shown to be potent inhibitors of hSERT. Conformational restriction of the homotryptamine side chain was attained by the insertion of a cyclopentyl ring, with the indole ring and the terminal dialkylamino group occupying the 1- and 3-positions, respectively. Nitrile and fluoro substitutions at the indole 5-position gave highest hSERT potency. Preferred cyclopentane ring stereochemistry in both series was cis (1S,3R for 5-CN compound 8a, 1R,3S for 5-F compound 9a). High hSERT binding affinity was observed for 8a and 9a (0.22 and 0.63 nM, respectively). The corresponding trans isomers were 4-9 times less potent. 8a, dosed at 1 and 3 mg/kg po, produced a robust, dose-dependent increase in extracellular serotonin in the frontal cortex of rats, similar to that induced by paroxetine at 5 mg/kg, po. By contrast, 9a did not produce a significant increase in extracellular serotonin in rat frontal cortex at 3 mg/kg po due to relatively low brain and plasma levels.
Assuntos
Ciclopentanos/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Triptaminas/síntese química , Animais , Disponibilidade Biológica , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Ciclopentanos/química , Ciclopentanos/farmacologia , Espaço Extracelular/metabolismo , Humanos , Microdiálise , Modelos Moleculares , Conformação Molecular , Ratos , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-Atividade , Triptaminas/química , Triptaminas/farmacologiaRESUMO
The synthesis and gamma-secretase inhibition data for a series of carbamate-appended N-alkylsulfonamides are described. Carbamate 54 was found to significantly reduce brain Abeta in transgenic mice. 54 was also found to possess markedly improved brain levels in transgenic mice compared to previously disclosed 1 and 2.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Carbamatos/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Camundongos , Camundongos Transgênicos , Relação Estrutura-AtividadeRESUMO
The synthesis and gamma-secretase inhibition data for a series of nitrogen-appended N-alkylsulfonamides (11-47) are described. Inhibition of brain Abeta in transgenic mice was demonstrated by two of these compounds (23 and 44).
Assuntos
Aminas/química , Aminas/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Alquilação , Aminas/síntese química , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Azóis/síntese química , Azóis/química , Azóis/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/metabolismo , Inibidores de Proteases/síntese química , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
A series of hybrid molecules containing the cyclopropylmethylamino side chain found in homotryptamine (1S,2S)-2c and an isosteric heteroaryl or naphthyl core were prepared and their binding affinities for the human serotonin transporter determined. The most potent isosteres were CN-substituted naphthalenes. These results demonstrate that isosteric aromatic cores which lack an H-bond donor site may be substituted for the indole nucleus without substantial loss in hSERT binding.
Assuntos
Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Triptaminas/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Compostos Heterocíclicos/síntese química , Humanos , Concentração Inibidora 50 , Conformação Molecular , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Relação Estrutura-AtividadeRESUMO
A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Ligação ProteicaRESUMO
A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a. The enantiomers of 6a were energy minimized and compared to other conformationally restricted SSRIs. Compound 6a was found to give a dose-response similar to the SSRI fluoxetine in microdialysis studies in rats.
Assuntos
Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Triptaminas/química , Animais , Cicloexenos/síntese química , Cicloexenos/química , Cicloexenos/farmacologia , Fluoxetina/química , Fluoxetina/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Microdiálise , Conformação Molecular , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Ratos , Inibidores Seletivos de Recaptação de Serotonina/síntese químicaRESUMO
BMS-299897 is a gamma-secretase inhibitor that has the potential for treatment of Alzheimer's disease. The metabolism of [(14)C]BMS-299897 was investigated in human liver microsomes, in rat, dog, monkey and human hepatocytes and in bile duct cannulated rats. Seven metabolites (M1-M7) were identified from in vitro and in vivo studies. LC-MS/MS analysis showed that M1 and M2 were regioisomeric acylglucuronide conjugates of BMS-299897. Metabolites M3, M4 and M6 were identified as monohydroxylated metabolites of BMS-299897 and M5 was identified as the dehydrogenated product of monooxygenated BMS-299897. In vivo, 52% of the radioactive dose was excreted in bile within 0-6 h from bile duct cannulated rats following a single oral dose of 15 mg/kg of [(14)C]BMS-299897. Glucuronide conjugates, M1 and M2 accounted for 80% of the total radioactivity in rat bile. In addition to M1 and M2, M7 was observed in rat bile which was identified as a glucuronide conjugate of an oxidative metabolite M5. For structure elucidation and pharmacological activity testing of the metabolites, ten microbial cultures were screened for their ability to metabolize BMS-299897 to form these metabolites. Among them, the fungus Cunninghamella elegans produced two major oxidative metabolites M3 and M4 that had the same HPLC retention time and mass spectral properties as those found in in vitro incubations. NMR analysis indicated that M3 and M4 were stereoisomers, with the hydroxyl group on the benzylic position. However, M3 and M4 were unstable and converted to their corresponding lactones readily. Based on x-ray analysis of the synthetically prepared lactone of M3, the stereochemistry of benzylic hydroxyl group was assigned as the R configuration. Both the hydroxy metabolites (M3 and M4) and the lactone of M3 showed gamma-secretase inhibition with IC(50) values similar to that of the parent compound. This study demonstrates the usefulness of microbial systems as bioreactors to generate metabolites of BMS-299897 in large quantities for structure elucidation and activity testing. This study also demonstrates the biotransformation profile of BMS-299897 is qualitatively similar across the species including rat, dog, monkey and human which provides a basis to support rat, dog and monkey as preclinical models for toxicological testing.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Butiratos/metabolismo , Cunninghamella/metabolismo , Inibidores Enzimáticos/metabolismo , Hidrocarbonetos Halogenados/metabolismo , Animais , Bile/metabolismo , Reatores Biológicos , Biotransformação , Butiratos/síntese química , Butiratos/farmacologia , Radioisótopos de Carbono , Linhagem Celular Tumoral , Células Cultivadas , Cães , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glucuronídeos/metabolismo , Hepatócitos/metabolismo , Humanos , Hidrocarbonetos Halogenados/síntese química , Hidrocarbonetos Halogenados/farmacologia , Macaca fascicularis , Masculino , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake inhibitors. Nitrile substituents at the 5 and 7 positions of the indole ring gave high affinity for hSERT, and the preferred cyclopropane stereochemistry was determined to be (1S,2S)-trans. The cis-cyclopropanes had 20- to 30-fold less affinity than the trans, and the preferred cis stereochemistry was (1R,2S)-cis. Substitution of the indole N-1 position with methyl or ethyl groups gave a 10- to 30-fold decrease in affinity for hSERT, suggesting either a hydrogen-bonding interaction or limited steric tolerance in the region of the indole nitrogen. Compound (+)-12a demonstrated potent hSERT binding (Ki = 0.18 nM) in vitro and was more than 1000-fold less potent at hDAT, hNET, 5-HT1A, and 5-HT6. In vivo, (+)-12a produced robust, dose-dependent increases in extracellular serotonin in rat frontal cortex typical of a selective serotonin reuptake inhibitor. The maximal response produced by (+)-12a was similar to that of fluoxetine but at an approximately 10-fold lower dose.
Assuntos
Ciclopropanos/síntese química , Indóis/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Triptaminas/síntese química , Animais , Cristalografia por Raios X , Ciclopropanos/química , Ciclopropanos/farmacologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Humanos , Indóis/química , Indóis/farmacologia , Microdiálise , Modelos Moleculares , Conformação Molecular , Ensaio Radioligante , Ratos , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Triptaminas/química , Triptaminas/farmacologiaRESUMO
Using a cell-based assay, we have identified optimal residues and key recognition elements necessary for inhibition of gamma-secretase. An (S)-hydroxy group or 3,5-difluorophenylacetyl group at the amino terminus and N-methyltertiary amide moiety at the carboxy terminus provided potent gamma-secretase inhibitors with an IC(50) <10 nM.
Assuntos
Amidas/farmacologia , Endopeptidases/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Amidas/síntese química , Secretases da Proteína Precursora do Amiloide , Animais , Ácido Aspártico Endopeptidases , Avaliação Pré-Clínica de Medicamentos , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Inibidores de Proteases/síntese química , Relação Estrutura-AtividadeRESUMO
Optimization of a benzyl piperazine pharmacophore produced N-acyl-4-indanyl-piperazines that bind with high affinity to melatonergic MT(2) receptors. (R)-4-(2,3-dihydro-6-methoxy-1H-inden-1-yl)-N-ethyl-1-piperazine-carboxamide fumarate (13) is a water soluble, selective MT(2) agonist, which produces advances in circadian phase in rats at doses of 1-56 mg/kg that are no different from those of melatonin at 1 mg/kg. Unlike melatonin, 13 produced only weak contractile effects in rat tail artery.
Assuntos
Piperazinas/síntese química , Piperazinas/farmacologia , Receptores de Superfície Celular/agonistas , Receptores Citoplasmáticos e Nucleares/agonistas , Células 3T3 , Adenilil Ciclases/metabolismo , Animais , Ritmo Circadiano/efeitos dos fármacos , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Piperazinas/metabolismo , Ratos , Ratos Long-Evans , Receptores de Superfície Celular/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de MelatoninaRESUMO
A new 5-HT(1A) silent antagonist 14 (5-HT(1A) IC(50)=2.2 nM) antagonizes the effects of agonists on reciprocal forepaw treading behavior, on neuronal firing in the rat dorsal raphé, and on 5-HT(1A) release in the raphé and hippocampus. While 14 alone was inactive in the social interaction paradigm, it completely reversed the social interaction activity of the serotonergic compounds (buspirone, 1, and 2).