RESUMO
We report the discovery of novel series of highly potent TLR7 agonists based on 8-oxoadenines, 1 and 2 by introducing and optimizing various tertiary amines onto the N(9)-position of the adenine moiety. The introduction of the amino group resulted in not only improved water solubility but also enhanced TLR7 agonistic activity. In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility. It also demonstrated a strong antitumor effect in vivo by intravenous administration in a tumor bearing mice model.
Assuntos
Adenina/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Receptor 7 Toll-Like/agonistas , Água/química , Adenina/administração & dosagem , Adenina/síntese química , Adenina/química , Adenina/farmacologia , Administração Intravenosa , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células HEK293 , Humanos , Camundongos , Estrutura Molecular , SolubilidadeRESUMO
The discovery of a novel class of nitric oxide synthase (NOS) inhibitors, 2-substituted 1,2-dihydro-4-quinazolinamines, and the related 4'-aminospiro[piperidine-4,2'(1'H)-quinazolin]-4'-amines is described. Members of both series exhibit nanomolar potency and high selectivity for the inducible isoform of the enzyme (i-NOS) relative to the constitutive isoforms in vitro. Efficacy in acute and chronic animal models of inflammatory disease following oral administration has also been demonstrated using these compounds.
Assuntos
Inibidores Enzimáticos/síntese química , Óxido Nítrico Sintase/antagonistas & inibidores , Quinazolinas/síntese química , Doença Aguda , Administração Oral , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Linhagem Celular , Doença Crônica , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Injeções Intravenosas , Isoenzimas/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II , Quinazolinas/química , Quinazolinas/farmacologia , Ratos , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
Systemic administration of a Toll-like receptor 7 (TLR7) agonist is effective to in suppressing Th2 derived inflammation, however systemic induction of various cytokines such as IL-6, IL-12, and type I interferon (IFN) is observed. This cytokine induction would be expected to cause flu-like symptoms. We have previously reported adenine compounds (3, 4) as interferon inducing agents acting as TLR7 agonists. To identify potent anti-inflammatory compounds without systemic side effects, a labile carboxylic ester as an antedrug functionality onto the N(9)-benzyl group of the adenine was introduced. We found that 9e was a potent TLR7 agonist (EC(50) 50 nM) and rapidly metabolized by human plasma (T(1/2) 2.6 min) to the pharmacologically much less active carboxylic acid 16. Intratracheal administration of 9e effectively inhibited allergen-induced airway inflammation without inducing cytokines systemically. Therefore, the TLR7 agonist with antedrug characteristics 9e (SM-324405) is a novel candidate for immunotherapy of allergic diseases.
Assuntos
Adenina/análogos & derivados , Receptor 7 Toll-Like/agonistas , Adenina/efeitos adversos , Adenina/síntese química , Adenina/farmacologia , Adenina/uso terapêutico , Animais , Ácidos Carboxílicos/química , Linhagem Celular , Estabilidade de Medicamentos , Humanos , Hipersensibilidade/metabolismo , Hipersensibilidade/terapia , Imunoterapia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interferons/biossíntese , Masculino , Ratos , Receptor 7 Toll-Like/metabolismoRESUMO
A Hit-to-Lead optimisation programme was carried out on the adamantane high throughput screening hit 1 resulting in the discovery of a number of potent P2X(7) antagonists.
Assuntos
Adamantano/análogos & derivados , Adamantano/farmacologia , Amidas/farmacologia , Antagonistas do Receptor Purinérgico P2 , Adamantano/síntese química , Amidas/síntese química , Desenho de Fármacos , Humanos , Cinética , Receptores Purinérgicos P2X7 , Relação Estrutura-AtividadeRESUMO
A Hit-to-Lead optimisation programme was carried out on the high throughput screening hit, the triazolethiol 1, resulting in the discovery of the potent, orally bioavailable triazolethiol CXCR2 receptor antagonist 45.
Assuntos
Receptores de Interleucina-8B/antagonistas & inibidores , Triazóis/farmacologia , Administração Oral , Animais , Quimiocinas/antagonistas & inibidores , Quimiocinas/metabolismo , Quimiocinas/farmacologia , Técnicas de Química Combinatória , Bases de Dados Factuais , Humanos , Estrutura Molecular , Ratos , Receptores de Interleucina-8B/química , Receptores de Interleucina-8B/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/metabolismoRESUMO
A hit-to-lead optimisation programme was carried out on the thiophenecarboxamide high throughput screening hits 1 and 2 resulting in the discovery of the potent and orally bioavailable IKK-2 inhibitor 22.