Edonentan Hydrate

Male Wistar rats were used for all experiments. The specificity of cardiac (18)F-FBzBMS uptake was determined in healthy animals (n = 23) using pretreatment with various blocking agents and doses. Myocardial infarction (MI) was induced by permanent left coronary ligation in 32 animals. Autoradiography was conducted to determine regional FBzBMS distribution relative to tissue perfusion at various times after MI. Histology and immunohistochemistry were performed for validation. The feasibility of in vivo detection of the tracer signal was tested using dedicated small-animal PET (n = 6).

At autoradiography, intravenous pretreatment with the selective ET-A blocker BMS-207940 reduced myocardial FBzBMS uptake by 93% ± 0.7%. Oral pretreatment with the clinical blocker bosentan resulted in a dose-dependent partial blockade (5 mg/kg, 48% ± 6%; 50 mg/kg, 61% ± 7%; and 100 mg/kg, 88% ± 0.7%). After MI, FBzBMS uptake was preserved in the infarct region from day 1 to month 6, whereas the perfusion tracer (201)Tl showed a persistent defect (MI-to-remote ratios: (201)Tl, 0.23 ± 0.28, 0.39 ± 0.07, 0.31 ± 0.07, 0.24 ± 0.12, 0.29 ± 0.10, and 0.23 ± 0.09; and FBzBMS, 0.94 ± 0.28, 0.92 ± 0.20, 0.88 ± 0.13, 0.82 ± 0.12, 0.80 ± 0.11, and 0.84 ± 0.08 at day 1, day 3, week 1, month 1, month 2, and month 6, respectively) (P < 0.01 vs. (201)Tl). Ex vivo analysis confirmed ET-A expression in the infarct area, where the signal was partially colocalized with CD31 expression on endothelial cells. In vivo small-animal PET successfully confirmed specific uptake and blockade of FBzBMS in healthy myocardium.

Cardiac uptake of the PET tracer (18)F-FBzBMS is specific for ET-A expression in rats, shows infarct-related alterations, and can be imaged noninvasively. Further efforts to establish myocardial ET-A imaging methodology are warranted, with the perspective of determining role, efficacy, and benefit of ET-A targeted drug treatment in cardiovascular disease.

A review.Herein, we address the pharmaceutical implications of a hitherto largely overlooked alternative source of drug chirality: atropisomerism.Atropisomers are conformers which, owing to steric or electronic constraints, interconvert slowly enough (by definition, with a half life of > 1000 s) that they can be isolated.'781 The stereochem. consequences of hindered rotation about a single bond can be such that an apparent single compound can actually be a mixture of two, or an apparently achiral compound can actually be racemic.If such pairs of stereoisomers are separable, then the implications for drug discovery may be similar to those of compounds with classical chiral centers.In the context of a lack of standard procedures for dealing with atropisomerism, and the absence of specific regulatory policies governing conformationally based stereochem., we explore some recent examples of atropisomeric compounds that have been or are in drug development.We also draw conclusions relating to potential strategies for design and development where atropisomerism is an issue.We expose and propose options for the management of atropisomerism, which, many view as a lurking menace with the potential to significantly increase the cost of pharmaceutical research and development if ignored.Atropisomerism may give rise to geometrical isomers, diastereoisomers, or enantiomers, all with the distinctive feature that they can in principle be equilibrated thermally.In the absence of specific regulatory policies, atropisomeric stereoisomers are best dealt with in the same way as stereoisomers with classical chiral centers, but with isomerization rates and where necessary, differential conformer populations taken into account.For racemic drug candidates, the FDA policy statement from 1992 emphasizes the importance of understanding the main therapeutic activities of the isomers through in vitro or in vivo studies.Studies of the pharmacokinetic behavior of the individual enantiomers carried out early in the development of drug candidates are also valuable.Knowledge gained from these studies can help guide the choice of development of a single enantiomer vs. a racemic mixtureDevelopment of a drug as a racemic mixture may be appropriate if the mixture is not reasonably separable (by synthetic methods, HPLC anal., etc.) or if racemization is rapid in vitro and/or in vivo (as in ibuprofen or thalidomide), thus making it futile to administer only the eutomer (more active isomer).However, it is nonetheless highly recommended that critical pharmacol. attributes related to the safety and efficacy of both isomers is investigated: overall, there must be an acceptable toxicol. profile and a suitable therapeutic window (in vitro, in animal models, and in humans).FDA website provides some useful guidance to their expectations for drug development in this context.Options for dealing with the phenomenon of atropisomerism can be implemented at the early stage of drug design.For example, it may be possible to make related analogs that have the following features: (1) symmetry about a hindered bond, thus eliminating a chiral axis; (2) faster rotation about a hindered bond, thus pushing the half-life for conformational interconversion down to the order of seconds; (3) further encumbrance about a hindered bond to produce separable atropisomers whose interconversion is negligibly slow (for example, half-lives of the order of millennia); or (4) introduction of a stable stereogenic center to perturb the population of interconverting atropisomers such that only one desirable conformation predominates.