RESUMO
Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvß1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvß1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvß1 inhibition.
Assuntos
Desenho de Fármacos , Receptores de Vitronectina , Animais , Ratos , Humanos , Receptores de Vitronectina/antagonistas & inibidores , Receptores de Vitronectina/metabolismo , Relação Estrutura-Atividade , Cirrose Hepática/tratamento farmacológico , Modelos Moleculares , Descoberta de Drogas , Ratos Sprague-Dawley , Masculino , Cristalografia por Raios X , Benzimidazóis/farmacologia , Benzimidazóis/química , Benzimidazóis/síntese químicaRESUMO
The mTOR kinase regulates a variety of critical cellular processes and has become a target for the treatment of various cancers. Using a combination of property-based drug design and Free-Wilson analysis, we further optimized a series of selective mTOR inhibitors based on the (S)-6a-methyl-6a,7,9,10-tetrahydro[1,4]oxazino[3,4-h]pteridin-6(5H)-one scaffold. Our efforts resulted in 14c, which showed similar in vivo efficacy compared to previous lead 1 at 1/15 the dose, a result of its improved drug-like properties.
RESUMO
Sign languages are frequently described as having three verb classes. One, 'agreeing' verbs, indicates the person/number of its subject and object by modification of the beginning and ending locations of the verb. The second, 'spatial' verbs, makes a similar appearing modification of verb movement to represent the source and goal locations of the theme of a verb of motion. The third class, 'plain' verbs, is characterized as having neither of these types of modulations. A number of researchers have proposed accounts that collapse all of these types, or the person-agreeing and spatial verbs. Here we present evidence from late learners of American Sign Language and from the emergence of new sign languages that person agreement and locative agreement have a different status in these conditions, and we claim their analysis should be kept distinct, at least in certain ways.