RESUMEN
A 58-year-old right-handed man presented with a 9-year history of stereotyped behaviors and auditory hallucinations. At 49 years of age, he began to complain about auditory hallucinations that said offensive things about him, and around the same time, he began exhibiting stereotyped behaviors. For example, he traveled the same long route from his office to home every evening. Disinhibitory behavior occurred at 53 years of age, and he was forced to retire at 54 years of age. After retirement, the patient stayed in bed or showed a stereotyped behavior of repeatedly going to a nearby shrine every day. The complaint of auditory hallucinations disappeared around this time. At 57 years of age, he began using a day service, and soon after, several stereotyped behaviors appeared in this setting as well. Brain magnetic resonance imaging at 59 years of age showed severe atrophy and knife-blade-like appearance in the bilateral temporal poles. A clinical diagnosis of frontotemporal dementia (FTD) was made based on the neurobehavioral, neuropsychological, and neuroimaging findings. FTD patients have been reported to show hallucinations very rarely. However, recent studies have reported that frontotemporal lobar degeneration (FTLD) patients with ubiquitin-positive and transactive response-DNA-binding protein-43 (TDP-43)-positive pathologies (FTLD-U-TDP) and FTD patients with progranulin gene mutations often develop hallucinations. The current patient may belong to this group of patients with similar neuropathological and molecular biological bases.
Asunto(s)
Demencia Frontotemporal/diagnóstico , Alucinaciones/diagnóstico , Demencia Frontotemporal/complicaciones , Alucinaciones/etiología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
To identify an orally available drug candidate, a series of 3-benzoylaminophenylacetic acids were synthesized and evaluated as prostaglandin D(2) (PGD(2)) receptor antagonists. Some of the compounds tested were found to exhibit excellent inhibitory activity against cAMP accumulation in human platelet rich plasma (hPRP), which is one of the indexes of DP antagonism. The optimization process including improvement of the physicochemical properties such as solubility, which may result in an improved pharmacokinetic (PK) profile, is presented. Optimized compounds were studied for their pharmacokinetics and in vivo potential. A structure-activity relationship study is also presented. Some of the test compounds were found to have in vivo efficacy towards the inhibition of PGD(2)-induced and OVA-induced vascular permeability in guinea pig conjunctiva.
Asunto(s)
Fenilacetatos/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Administración Oral , Animales , Células CHO , Cricetinae , Cricetulus , Cobayas , Humanos , Modelos Moleculares , Fenilacetatos/química , Ratas , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relación Estructura-ActividadRESUMEN
To identify new cost-effective prostaglandin D2 (DP) receptor antagonists, a series of novel 3-benzoylaminophenylacetic acids were synthesized and biologically evaluated. Among those tested, some representative compounds were found to be orally available. Receptor selectivity and rat PK profiles were also evaluated. The structure-activity relationship (SAR) study is presented.
Asunto(s)
Benzamidas/farmacología , Diseño de Fármacos , Fenilacetatos/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Animales , Benzamidas/síntesis química , Benzamidas/química , Unión Competitiva/efectos de los fármacos , Células CHO , Cricetinae , Relación Dosis-Respuesta a Droga , Masculino , Conformación Molecular , Fenilacetatos/síntesis química , Fenilacetatos/química , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
A series of N-benzoyl-2-methylindole-3-acetic acids were synthesized and biologically evaluated as prostaglandin (PG) D2 receptor antagonists. Some of the selected compounds significantly inhibited OVA-induced vascular permeability in guinea pig conjunctiva after oral dosing. Structure-activity relationship study is presented.
Asunto(s)
Permeabilidad Capilar/efectos de los fármacos , Indoles/química , Indoles/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/antagonistas & inhibidores , Receptores de Prostaglandina/metabolismo , Animales , Células CHO , Conjuntiva/irrigación sanguínea , Cricetinae , Cricetulus , Descubrimiento de Drogas , Cobayas , HumanosRESUMEN
A series of 3-[2-{[(3-methyl-1-phenylbutyl)amino]carbonyl}-4-(phenoxymethyl)phenyl]propanoic acid analogs were synthesized and evaluated for their in vitro potency. In most cases, introduction of one or two substituents into the two phenyl moieties resulted in the tendency of an increase or retention of in vitro activities. Several compounds, which showed excellent subtype selectivity, were evaluated for their inhibitory effect against PGE(2)-induced uterine contraction in pregnant rats, which is thought to be mediated by the EP3 receptor subtype. The structure-activity relationships (SARs) are also discussed.
Asunto(s)
Propionatos/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Femenino , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Embarazo , Propionatos/química , Propionatos/farmacocinética , Ratas , Subtipo EP3 de Receptores de Prostaglandina E , Contracción Uterina/efectos de los fármacosRESUMEN
A series of 4-([2-[alkyl(phenylsulfonyl)amino]phenoxy]methyl)benzoic acids were identified as functional PGE(2) antagonists with selectivity for the EP1 receptor subtype starting from a chemical lead 1, which was found while screening our in-house compound library. Discovery of the optimized analogs 21-23 is presented here and structure-activity relationships (SAR) are also discussed.
Asunto(s)
Analgésicos/farmacología , Benzoatos/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Sulfonamidas/farmacología , Analgésicos/síntesis química , Animales , Benzoatos/síntesis química , Sitios de Unión , Células CHO , Cricetinae , Receptores de Prostaglandina E/metabolismo , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-Actividad , Sulfonamidas/síntesis químicaRESUMEN
A series of N-(p-alkoxy)benzoyl-5-methoxy-2-methylindole-3-acetic acids and N-(p-butoxy)benzoyl-2-methylindole-4-acetic acid were discovered as new chemical leads for a prostaglandin D2 (PGD2) receptor antagonist. Most of them exhibited PGD2 receptor binding and blocked cyclic adenosine 3',5'-monophosphate (cAMP) formation in vitro. In particular, 2-methylindole-4-acetic acid analog 1 showed markedly increased receptor affinity and cAMP antagonist activity. Chemistry and structure activity relationship (SAR) data are also presented.
Asunto(s)
Ácidos Indolacéticos/síntesis química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Animales , Área Bajo la Curva , Unión Competitiva/fisiología , Células CHO , Cricetinae , AMP Cíclico/antagonistas & inhibidores , AMP Cíclico/metabolismo , Semivida , Ácidos Indolacéticos/química , Ácidos Indolacéticos/farmacocinética , Indometacina/análogos & derivados , Indometacina/química , Indometacina/farmacocinética , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratas , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Relación Estructura-ActividadRESUMEN
The process of discovery for highly potent prostaglandin D(2) (PGD(2)) receptor antagonists is reported. A series of N-(p-alkoxy)benzoyl-2-methylindole-4-acetic acids were synthesized and identified as a new class of selective PGD(2) receptor antagonists. Most of them exhibited strong PGD(2) receptor antagonism in binding studies and the cAMP formation assay. The structure-activity relationships (SAR), including subtype selectivity of the synthesized compounds, are also discussed.
Asunto(s)
Antialérgicos/farmacología , Ácidos Indolacéticos/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Antialérgicos/síntesis química , Sitios de Unión , AMP Cíclico/metabolismo , Diseño de Fármacos , Ácidos Indolacéticos/química , Relación Estructura-ActividadRESUMEN
A series of Indomethacin analogs were synthesized and biologically evaluated. Among the compounds tested, N-(p-butoxy)benzoyl-2-methylindole-4-acetic acid 2 was discovered as a new chemical lead for a prostaglandin D2 (PGD2) receptor antagonist. Structure-activity relationship data are also presented.
Asunto(s)
Antagonistas de Prostaglandina/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Ratones , Antagonistas de Prostaglandina/metabolismo , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMEN
The process of discovering a series of N-(p-alkoxy)benzoyl-2-methylindole-4-acetic acid analogs is presented since these compounds represent a new class of potent, selective, and orally active prostaglandin D2 (PGD2) receptor antagonists. Most of these compounds exhibit strong PGD2 receptor binding and PGD2 receptor antagonism in cAMP formation assays. When given orally, these new antagonists dramatically suppress allergic inflammatory responses, such as the PGD2-induced or OVA-induced increase of vascular permeability. Structure-activity relationship (SAR) data are also discussed.
Asunto(s)
Antialérgicos/química , Antialérgicos/farmacología , Ácidos Indolacéticos/química , Ácidos Indolacéticos/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Administración Oral , Animales , Antialérgicos/administración & dosificación , Cobayas , Humanos , Ácidos Indolacéticos/administración & dosificación , Ratas , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMEN
A series of N-(p-alkoxy)benzoyl-2-methylindole-4-acetic acids were synthesized and evaluated for prostaglandin D(2) (DP) receptor affinity and antagonist activity. Some of them exhibited strong receptor binding and were potent in the cAMP formation assays. These antagonists also suppressed allergic inflammatory responses such as the PGD(2)-induced increase of microvascular permeability. Structure-activity relationship (SAR) data are presented.