Ligand bias prevents class equality among beta-blockers.

ß-Blockers are used for a wide range of diseases from hypertension to glaucoma. In some diseases/conditions all ß-blockers are effective, while in others only certain subgroups are therapeutically beneficial. The best-documented example for only a subset of ß-blockers showing clinical efficacy is in heart failure, where members of the class have ranged from completely ineffective, to drugs of choice for treating the disease. Similarly, ß-blockers were tested in murine asthma models and two pilot clinical studies. A different subset was found to be effective for this clinical indication. These findings call into question the current system of classifying these drugs. To consider 'ß-blockers', as a single class is misleading when considering their rigorous pharmacological definition and their appropriate clinical application.

From ATP to AZD6140: the discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis.

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.