RESUMO
A one-step transformation to produce 8,9-dihydrocannabidiol (H2CBD) and related "neocannabinoids" via controlled Friedel-Crafts reactions is reported. Experimental and computational studies probing the mechanism of neocannabinoid synthesis from cyclic allylic alcohol and substituted resorcinol reaction partners provide understanding of the kinetic and thermodynamic factors driving regioselectivity for the reaction. Herein, we present the reaction scope for neocannabinoid synthesis including the production of both normal and abnormal isomers under both kinetic and thermodynamic control. Discovery and optimization of this one-step protocol between various allylic alcohols and resorcinol derivatives are discussed and supported with density functional theory calculations.
RESUMO
New cholecystokinin-1 receptor (CCK1R) agonist 'triggers' were identified using iterative library synthesis. Structural activity relationship studies led to the discovery of compound 10e, a potent CCK1R agonist that demonstrated robust weight loss in a diet-induced obese rat model with very low systemic exposure. Pharmacokinetic data suggest that efficacy is primarily driven through activation of CCK1R's located within the intestinal wall.
Assuntos
Amidas/síntese química , Descoberta de Drogas , Piperidinas/síntese química , Receptor de Colecistocinina A/agonistas , Amidas/química , Amidas/farmacologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Obesos , Piperidinas/química , Piperidinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Redução de Peso/efeitos dos fármacosRESUMO
A series of N-benzylpyroglutamyl-L-phenylalanine derivatives bearing carbamoyl substituents in the 3- or 4-positions was prepared and assayed for inhibition of the interaction between VCAM and VLA-4. Potent inhibition was observed in a number of analogues with substitution in the 4-position favored over the 3-position. A crystal structure of the key intermediate 25 indicates that it accesses a low energy conformation which closely matches key pharmacophores of a structurally characterized cyclic peptide.