RESUMO
A new series of 2-(benzyloxy)benzamides are presented that are potent functional antagonists of TRPM8 and possess improved LipE and LE compared to the original lead. They were discovered through a series of compound libraries and we present a powerful visualization method for the chemical space explored with each library. Remarkably this new series originated from the highest risk design strategy where compounds were synthesised with the least degree of similarity to the lead structure.
Assuntos
Benzamidas/farmacologia , Canais de Cátion TRPM/antagonistas & inibidores , Animais , Desenho de Fármacos , Descoberta de Drogas , Humanos , Ratos , Relação Estrutura-AtividadeRESUMO
A series of p-hydroxybenzenesulphonamides ERß receptor agonists were discovered and several compounds identified had excellent selectivity over the related ERα receptor. One of these, compound 11, had an interesting binding conformation determined by X-ray and represents an excellent starting point in the quest for further selective ERß agonists.
Assuntos
Descoberta de Drogas , Receptor beta de Estrogênio/agonistas , Sulfonamidas/química , Sulfonamidas/farmacologia , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos , Ligantes , Modelos Químicos , Ligação Proteica , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismoRESUMO
A second wave of potential SSRIs with high ease of synthetic accessibility were designed based on the reported selective serotonin re-uptake inhibitor litoxetine and our own previous work in this area. Preparation and subsequent optimisation yielded a range of potent and highly selective SSRIs.
Assuntos
Antidepressivos/química , Inibidores Seletivos de Recaptação de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Inibidores da Captação Adrenérgica/química , Inibidores da Captação Adrenérgica/farmacologia , Antidepressivos/síntese química , Antidepressivos/farmacologia , Inibidores da Captação de Dopamina/química , Inibidores da Captação de Dopamina/farmacologia , Desenho de Fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
The reported selective serotonin Re-uptake Inhibitor Litoxetine was used as the starting point in the design of a range of potential SSRIs with high ease of synthetic accessibility. Preparation and subsequent optimization yielded a range of potent and highly selective SSRIs.
Assuntos
Desenho de Fármacos , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Linhagem Celular , Humanos , Piperidinas/síntese química , Piperidinas/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of thio-alkyl containing diphenylethers were designed and evaluated, as a strategy to competitively direct metabolism away from unwanted amine N-demethylation and deliver a pharmacologically inactive S-oxide metabolite. Overall, sulfonamide 20 was found to possess the best balance of target pharmacology, pharmacokinetics and metabolism profile.
Assuntos
Benzilaminas/síntese química , Benzilaminas/farmacologia , Éteres Fenílicos/síntese química , Éteres Fenílicos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Benzilaminas/química , Técnicas de Química Combinatória , Humanos , Estrutura Molecular , Éteres Fenílicos/química , Inibidores Seletivos de Recaptação de Serotonina/química , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
A series of substituted benzylamines 2-48 were prepared as part of a strategy to identify structurally differentiated and synthetically more accessible selective serotonin reuptake inhibitors, relative to clinical candidate 1. In particular, 44 and 48; demonstrated low nanomolar potency and good selectivity, in a structurally simplified template and, in vivo, very low Vdu, significantly lower than l, and a more rapid T(max), consistent with our clinical objectives.
Assuntos
Benzilaminas/química , Química Farmacêutica/métodos , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cinética , Modelos Químicos , Conformação Molecular , Receptores de Serotonina/metabolismo , Serotonina/química , Serotonina/metabolismo , Relação Estrutura-AtividadeRESUMO
Single enantiomer (SS) and (RR) 2-[(phenoxy)(phenyl)methyl]morpholine derivatives 5, 8-23 are inhibitors of monoamine reuptake. Target compounds were prepared using an enantioselective synthesis employing a highly specific enzyme-catalysed resolution of racemic n-butyl 4-benzylmorpholine-2-carboxylate (26) as the key step. Structure-activity relationships established that serotonin and noradrenaline reuptake inhibition are functions of stereochemistry and aryl/aryloxy ring substitution. Consequently, selective SRI, selective NRI and dual SNRIs were all identified. One of these compounds, a potent and selective dual SNRI, (SS)-5a was selected as a candidate for further pre-clinical evaluation.
Assuntos
Desenho de Fármacos , Morfolinas/síntese química , Morfolinas/farmacologia , Norepinefrina/metabolismo , Serotonina/metabolismo , Células Cultivadas , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estrutura Molecular , Morfolinas/química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of sertraline analogues 4-39 which possess polar groups on the fused tetrahydronaphthalene ring, targeting reduced V(d) as a strategy to reduce T(max) and increase rate of elevation of central 5-HT levels, were prepared. These studies led to the successful identification of 22a, which demonstrated equivalent pharmacology and metabolic stability to 1, but which possessed greatly reduced V(d) leading to significantly shorter T(max), in rat pharmacokinetic studies.
