RESUMO
Many lead compounds with the potential to progress to viable drug candidates have been identified from libraries during the past two years. There are two key strategies most often employed to find leads from libraries: first, high-throughput biological screening of corporate compound collections; and second, synthesis and screening of project-directed libraries (i.e. target-based libraries). Numerous success stories, including the discovery of several clinical candidates, testify to the utility of chemical library collections as proven sources of new leads for drug development.
Assuntos
Técnicas de Química Combinatória/tendências , Desenho de Fármacos , Biblioteca de Peptídeos , Animais , Humanos , Modelos MolecularesRESUMO
Aminomethyl tetrahydronaphthalene biphenyl carboxamide MCH-R1 antagonists with greater selectivity over hERG were identified. SAR studies addressing two distinct alternatives for structural modifications leading to improve hERG selectivity are described.
Assuntos
Compostos de Bifenilo/farmacologia , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Naftalenos/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Compostos de Bifenilo/síntese química , Canal de Potássio ERG1 , Ergolinas/farmacologia , Humanos , Indicadores e Reagentes , Mianserina/farmacologia , Naftalenos/síntese química , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
High-throughput screening of the P&GP corporate repository against several protein tyrosine phosphatases identified the sulfamic acid moiety as potential phosphotyrosine mimetic. Incorporation of the sulfamic acid onto a 1,2,3,4-tetrahydroisoquinoline scaffold provided a promising starting point for PTP1B inhibitor design.
Assuntos
Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Ácidos Sulfônicos/farmacologia , Tetra-Hidroisoquinolinas/química , Sítios de Ligação , Ligação Competitiva , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Ligantes , Modelos Moleculares , Mimetismo Molecular , Fosfotirosina/metabolismo , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteínas Tirosina Fosfatases/química , Proteínas Tirosina Fosfatases/metabolismo , Relação Estrutura-Atividade , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/química , Domínios de Homologia de srcRESUMO
The scope and limitations of the solid-supported synthesis of a bicyclic diketopiperazine, an internal, putative peptide beta-turn mimetic, are presented. The 4CC multicomponent Ugi reaction of alpha-N-Boc-diaminopropionic acid resin ester (an amine input), optically active alpha-bromoacid, aldehyde, and isocyanide is the key step in the proposed synthetic protocol. Application of cyclitive cleavage as the final step led to desired products in high purity.