RESUMO
Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [(3)H]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H(4) antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.
Assuntos
Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Ligação Competitiva , Linhagem Celular Tumoral , Quimiotaxia de Leucócito/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/farmacocinética , Humanos , Indóis/síntese química , Indóis/farmacocinética , Indóis/farmacologia , Mastócitos/efeitos dos fármacos , Camundongos , Piperazinas/farmacocinética , Ratos , Receptores Histamínicos , Receptores Histamínicos H4RESUMO
The Orphan Drug Act has been successful in providing incentives to find cures for orphan diseases. However, many orphan diseases are still without cure. Therefore, the 114th Congress has introduced the 21st Century Cures Act and the Orphan Product Extension Now Accelerating Cures and Treatment Act of 2015 to further provide incentives to innovators to repurpose existing drugs for treatment of these orphan diseases. However, these bills are currently pending and their incentives might not go far enough.
RESUMO
Following the discovery of the human histamine H4 receptor, a high throughput screen of our corporate compound collection identified compound 6 as a potential lead. Investigation of the SAR resulted in the discovery of novel compounds 10e and 10l, which are the first potent and selective histamine H4 receptor antagonists to be described.
Assuntos
Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Receptores de Superfície Celular/efeitos dos fármacos , Receptores Acoplados a Proteínas G , Receptores Histamínicos , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Antagonistas dos Receptores Histamínicos/metabolismo , Humanos , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Cinética , Ligantes , Neurônios/citologia , Piperazinas/metabolismo , Ensaio Radioligante , Ratos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores Histamínicos H4 , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , TransfecçãoRESUMO
The characterization and anatomical distribution of 5-hydroxytryptamine (5-HT)(7) receptor binding sites in brain tissue has been hampered by the lack of a specific radioligand. In the present autoradiographic study, we took advantage of 5-HT(1A) knockout and 5-HT(1A/1B) double-knockout mice to revisit the pharmacological characterization and anatomical localization of 5-HT(7) binding sites in mouse brain using [(3)H]5-carboxamidotryptamine (5-CT) and [(3)H]8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT). The distribution pattern of [(3)H]5-CT binding sites (2 nM) in the brain of mice lacking the 5-HT(1A/1B) receptor was scarce and confined to the septum, globus pallidus, thalamus, hypothalamus, amygdala, cortex, and substantia nigra. The low densities of [(3)H]5-CT binding sites detected in septum, thalamus, hypothalamus, amygdala, and cortex were displaced by 10 microM of the selective 5-HT(7) receptor antagonist (R)-3-(2-(2-(4-methylpiperidin-1-yl) ethyl)pyrrolidine-1-sulfonyl) phenol (SB-269970). The SB-269970-insensitive [(3)H]5-CT binding sites detected in globus pallidus and substantia nigra of 5-HT(1A/1B) knockout mice were displaced by N-[3-(2-dimethylamino)ethoxy-4-methoxy-phenyl]-2'-methyl-4'- (5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide hydrochloride (SB-216641) (1 microM), demonstrating the 5-HT(1D) nature of these binding sites. In contrast to the low densities of [(3)H]5-CT binding sites, high-to-moderate densities of [(3)H]8-OH-DPAT binding sites (10 nM) were found throughout the brain of 5-HT(1A) and 5-HT(1A/1B) knockout mice (olfactory system, septum, thalamus, hypothalamus, amygdala, CA3 field of the hippocampus, cortical mantle, and central gray). These [(3)H]8-OH-DPAT binding sites were displaced by 10 microM SB-269970, risperidone, and methiothepin but not by pindolol, N-tert-butyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylpropanamide (WAY- 100135), or citalopram. We conclude that despite its high affinity for the 5-HT(7) receptor in tissue homogenates, [(3)H]5-CT is not a good tracer for measuring 5-HT(7) receptor binding sites autoradiographically. Also, the lower affinity ligand [(3)H]8-OH-DPAT is a much better tracer for autoradiographic studies at the 5-HT(7) receptor binding sites.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina , Química Encefálica/genética , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina , Agonistas do Receptor de Serotonina , Serotonina/análogos & derivados , Animais , Autorradiografia , Encéfalo/anatomia & histologia , Camundongos , Camundongos Knockout , Fenóis/farmacologia , Ensaio Radioligante , Receptor 5-HT1B de Serotonina , Receptores de Serotonina/genética , Receptores 5-HT1 de Serotonina , Sulfonamidas/farmacologiaRESUMO
Continued exploration of the SAR around the lead imidazopyridine histamine H(3) antagonist 1 has led to the discovery of several related series of heterocyclic histamine H(3) antagonists. The synthesis and SAR of indolizine, indole and pyrazolopyridine based compounds are now described.