Discovery of new quinoline ether inhibitors with high affinity and selectivity for PDGFR tyrosine kinases.

A new series of quinoline ether inhibitors, which potently and selectively inhibit PDGFR tyrosine kinases, is described in this Letter. Compounds 23 and 33 are selective, low nanomolar inhibitors of PDGFRα and ß, display good pharmacokinetics in rat and dog and are active in vivo at low doses when given orally twice daily. Further evaluation of these compounds is warranted.

Discovery of AZD2932, a new Quinazoline Ether Inhibitor with high affinity for VEGFR-2 and PDGFR tyrosine kinases.

A new series of Quinazoline Ether Inhibitor which potently inhibits VEGFR-2 and PDGFR tyrosine kinases is described here. In vitro, pharmacokinetics and in vivo evaluations led to the selection of AZD2932.

Metabolic stability: main enzymes involved and best tools to assess it.

The introduction of in vitro tools to predict clearance in the early discovery process has led to new ways of working. Combined with metabolite identification, such tools have allowed design of compounds with low clearance. Encouraged by the success of such an approach and by the better knowledge of the enzyme involved in the metabolism, in vitro teams have begun to develop a plethora of assays to assess the metabolic clearance, understand the route of metabolism, and predict the human clearance. Although the diversity of assays may have allowed a more thorough approach to addressing specific issues, in the time of budget constrictions, limited access to resources and materials in vitro teams have now to decide what are the 'must have' and 'nice to have' assays to enable them to help as efficiently as possible projects at the discovery stage. Reducing the number of assays and focusing on the most relevant ones is an option to consider. Knowledge of the main enzymes involved in the drug metabolism should help to select the most relevant in vitro tools. Although the systems presented here have their merits, the author proposes that hepatocytes should be considered as the in vitro tool of choice.

In vitro metabolism of tresperimus by human vascular semicarbazide-sensitive amine oxidase.

Tresperimus (Cellimis), a new immunosuppressive agent is mainly eliminated through an extensive nonhepatic metabolism, in which the oxidative deamination of the primary amine of the drug takes a preponderant part. We have previously demonstrated the ability of human plasma semicarbazide-sensitive amine oxidase (SSAO) to catalyze this reaction. Therefore, the suitability of human umbilical artery, a tissue combining a high SSAO activity with monoamine oxidase activity, to study tresperimus metabolism was tested, and the kinetic behavior of tissue-bound SSAO was compared with that of plasma soluble SSAO. All the oxidized metabolites resulting from the deamination of tresperimus and of two other metabolites, desaminopropyl derivatives of tresperimus and guanidinohexylamine, were formed in vascular homogenates. Chemical inhibition experiments demonstrated the major involvement of SSAO in the metabolism of these three compounds at physiologically relevant concentrations. The microsomal fraction was used to characterize tresperimus deamination. Tissue-bound and soluble SSAO exhibited similar K(m) values for the drug and K(I) values of tresperimus toward benzylamine metabolism, a classical SSAO substrate. The kinetic behavior of both enzymes seemed to argue in favor of a same catalytic entity. Human umbilical artery constituted a relevant in vitro model to demonstrate the predominant role of SSAO in tresperimus metabolism. Our results suggest that the possible role of SSAO as Phase I oxidative enzymes has to be considered in metabolism studies for drugs encompassing primary amine.