RESUMO
A series of N-1,3 disubstituted 2,1,3-benzothiadiazine derivatives (BTDs) were synthesized and evaluated for their inhibitory activity versus enzymatic isoform PDE4 extracted from U937 cell line. Some of the tested compounds showed a high PDE4 inhibitory activity at 100 microM and the IC(50) value of the most interesting terms were evaluated. The structure-activity relationships of these compounds showed that the 3,5-di-tert-butyl-4-hydroxybenzyl moiety at N-1 position is important to obtain activity at micromolar level as previously reported. For the same compounds the antioxidant activity were evaluated highlighting 14 as the most significative one. The introduction of other bulky substituents in N-1 position is detrimental.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Benzotiadiazinas/síntese química , Benzotiadiazinas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Benzotiadiazinas/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Humanos , Isoenzimas/antagonistas & inibidores , Estrutura Molecular , Relação Estrutura-Atividade , Células U937RESUMO
A series of new 1,2,4-benzothiadiazine derivatives with an arylpiperazine mojety linked at position 3 of the heterocyclic ring were synthesized and assessed for their pharmacological profiles at alpha(1)-adrenoceptor subtypes (alpha(1A), alpha(1B) and alpha(1D)) by functional experiments and by in vitro binding studies at human cloned 5-HT(1A) receptor. Compound 1 was identified as a novel alpha(1D) antagonist (pK(b)alpha(1D)=7.59; alpha(1D)/alpha(1A)>389; alpha(1D)/alpha(1B)=135) with high selectivity over 5-HT(1A) receptor (5-HT(1A)/alpha(1D)<0.01), while compound 6, a 3,4-dihydro-derivative, was characterized as a novel 5-HT(1A) receptor ligand, highly selective over alpha(1D)-adrenoceptor subtype (pK(i)5-HT(1A)=8.04; 5-HT(1A)/alpha(1D)=1096). Further pharmacological studies demonstrated that 6 is a partial agonist at 5-HT(1A) receptor (E(max)=23, pD(2)=6.92).
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Benzotiadiazinas/síntese química , Agonistas do Receptor 5-HT1 de Serotonina , Animais , Aorta Torácica , Benzotiadiazinas/farmacologia , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Técnicas In Vitro , Ligantes , Masculino , Ratos , Receptores Adrenérgicos alfa 1/metabolismo , Baço , Relação Estrutura-Atividade , Ducto DeferenteRESUMO
A series of 2,1,3- and 1,2,4-benzothiadiazine derivatives (BTDs) were synthesized and evaluated for their inhibitory activity versus enzymatic isoforms PDE3, PDE4 and PDE7. The compounds characterized by the 3,5-di-tert-butyl-4-hydroxybenzyl moiety at N1 position of 2,1,3-benzothiadiazine core (8, 13, 18), were found active and selective at micromolar level versus PDE4 and could be studied as new leads for the treatment of asthma and COPD (Chronic Obstructive Pulmonary Disease). The antioxidant activity evaluation on the same compounds highlighted 13 as the most significative. Molecular modelling studies gave further support to biological results and suggested targeted modifications so as to improve their potency.
