RESUMEN
Starting with the molecular scaffold of the DA(2)/ß(2) dual agonist sibenadet (Viozan™), a number of molecular changes were incorporated, which were designed to increase the potency and selectivity of the target molecule, and improve its pharmacokinetics. Through this process a novel, high potency, full ß(2)-agonist with high selectivity and long duration capable of being dosed once daily has been discovered.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/química , Broncodilatadores/química , Receptores Adrenérgicos beta 2/química , Tiazoles/química , Agonistas de Receptores Adrenérgicos beta 2/síntesis química , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Animales , Broncodilatadores/síntesis química , Broncodilatadores/farmacocinética , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Cobayas , Receptores Adrenérgicos beta 2/metabolismo , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacocinéticaRESUMEN
Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y(12) receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.
Asunto(s)
Adenosina Trifosfato/uso terapéutico , Adenosina/análogos & derivados , Proteínas de la Membrana/antagonistas & inhibidores , Antagonistas del Receptor Purinérgico P2 , Trombosis/prevención & control , Adenosina/uso terapéutico , Administración Oral , Animales , Humanos , Receptores Purinérgicos P2Y12 , TicagrelorRESUMEN
We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.