RESUMEN
Optimization of the biological activity of a new class of non-peptidyl, pyridazinone derived human melanocortin subtype-4 receptor agonists is disclosed.
Asunto(s)
Diseño de Fármacos , Piridazinas/química , Piridazinas/farmacología , Receptor de Melanocortina Tipo 4/agonistas , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Piridazinas/síntesis química , Receptor de Melanocortina Tipo 4/metabolismo , Relación Estructura-ActividadRESUMEN
Efficient routes to access the 2", 3", 4", and 6" registers of the nodulisporic acid (NsA) side chain are disclosed. A mild one-carbon, Ph(2)CdoublebondNCH(2)CtriplebondN mediated homologation of NsA's 3"-aldehyde permitted access to the 4"-register. Curtius reaction of NsA's 3"-acid yielded the corresponding 2"-aldehyde 4 from which the unnatural Delta(2",3")-olefin isomer 2b was obtained. In addition, Arndt-Eistert reactions of the parent NsA permitted a one-carbon homologation to the 6" register. These efforts identified new analogues with significant flea activity and illustrated the biological significance of unsaturation at the 1",2" register.
Asunto(s)
Indoles/química , Insecticidas/síntesis química , Alquenos , Animales , Relación Dosis-Respuesta a Droga , Indoles/farmacología , Insecticidas/farmacología , Siphonaptera/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
An efficient synthesis of the truncated 3"-aldehyde (3) from nodulisporic acid A (1) under mild conditions is described. Further oxidation of 3 to 3"-carboxylic acid (4) and its subsequent oxidative degradation produced 1"-aldehyde (5). These new derivatives are versatile intermediates for the preparation of new, side chain modified derivatives of nodulisporic acid A. [reaction: see text]