Potent and selective nonpeptidic inhibitors of procollagen C-proteinase.

6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2-6 nM) with improved TED flux.

Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines.

1-isoquinolinylguanidines were previously disclosed as potent and selective inhibitors of urokinase-type plasminogen activator (uPA). Further investigation of this template has revealed that incorporation of a 7-sulfonamide group furnishes a new series of potent and highly selective uPA inhibitors. Potency and selectivity can be achieved with sulfonamides derived from a variety of amines and is further enhanced by the incorporation of sulfonamides derived from amino acids.

Integrative pharmacology and drug discovery--is the tide finally turning?

In vivo animal experiments are essential (and a regulatory requirement) to demonstrate the potential efficacy, safety and pharmacodynamic/pharmacokinetic profile of candidate drugs. However, the number of pharmacologists (and other bioscientists) with integrative (in vivo) pharmacology skills has been in decline for a number of years, as have the opportunities for students to learn such skills. This article reviews some recent initiatives that are underway to rebuild this essential skills base in the United Kingdom and the United States.

Effect of endothelin antagonists on the renal haemodynamic and tubular responses to ischaemia-reperfusion injury in anaesthetised rats.

In this investigation we have evaluated whether blockade of endothelin receptors influenced the renal haemodynamic and excretory responses to a period of ischaemia and reperfusion in the anaesthetised rat. The renal artery was occluded for 30 min and renal haemodynamic and excretory function followed for 90 min of reperfusion while either saline, the non-selective endothelin 1 receptor (ET(A)/ET(B)) antagonist SB209670 or the selective ET(A) receptor antagonist UK-350,926 was infused. In the post-ischaemic period, renal cortical and medullary perfusions were reduced by 40-50 %.

The effect of endothelin antagonists on renal ischaemia-reperfusion injury and the development of acute renal failure in the rat.

Background: It is recognized that endothelins are released in response to hypoperfusion and anoxia of the kidney and may be responsible for the consequent deterioration in renal function. This study examined the ability of a non-selective (SB209670) and ET(A)-selective (UK-350,926) endothelin antagonist to attenuate ischaemia-induced renal failure in unilaterally nephrectomized rats.

Methods: The animals were anaesthetized, drug infusion commenced, and the renal artery occluded for 30 min.