RESUMEN
Dental patients who experience comorbid psychiatric and medical conditions present an elevated risk of medication misuse, abuse, substance use disorders, and overdose. The authors review the role of notable comorbidities in predicting the development of substance use disorder, including medical, psychiatric, and other psychosocial factors that can be assessed in general dental practice. Psychiatric disorders commonly cooccur with substance abuse, and these typically include anxiety disorders, mood disorders (major depression, bipolar), posttraumatic stress, as well as sleep and eating disorders. Medical disorders commonly found to be present with substance use disorders are also reviewed, including common cardiovascular and pulmonary disorders.
Asunto(s)
Sustancias Controladas , Trastornos Relacionados con Sustancias/epidemiología , Trastornos de Ansiedad/epidemiología , Comorbilidad , HumanosRESUMEN
Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.
Asunto(s)
Antineoplásicos/farmacología , Cinamatos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Indazoles/farmacología , Receptores de Estrógenos/antagonistas & inhibidores , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Tamoxifeno/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cinamatos/síntesis química , Cinamatos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Indazoles/síntesis química , Indazoles/química , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Estructura Molecular , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/química , Relación Estructura-Actividad , Tamoxifeno/síntesis química , Tamoxifeno/químicaRESUMEN
Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.
