No abstract

1 Myocardial ischemia/reperfusion is associated with inflammation, apoptosis and necrosis. During this process, c-jun N-terminal kinase is activated in cardiac myocytes resulting in apoptosis. 2 This study investigates the effects of AS601245, a nonpeptide ATP competitive JNK inhibitor, on infarct size caused by myocardial ischemia/reperfusion in anaesthetized rats. The left descending coronary artery of anaesthetized rats was occluded for 30 min and then reperfused for 3 h. AS601245 was administered 5 min before the end of the ischemia period as an i.v. bolus (1.5, 4.5 or 15 mg kg À1 i.v.) followed by continuous i.v. infusion (18, 55 and 183 mg kg À1 min À1, respectively) during reperfusion. Controls received saline only. 3-Aminobenzamide, a poly(ADP-ribose) polymerase inhibitor, was used as reference compound at 10 mg kg À1 i.v. bolus plus 0.17 mg kg À1 min À1 continuous infusion. 3 AS601245 significantly reduced infarct size at 4.5 mg kg À1 (À44%; Po0.001) and 15 mg kg À1 i.v. (À40.3%; Po0.001) similarly to 3-aminobenzamide (À44.2%; Po0.001). This protective effect was obtained without affecting hemodinamics or reducing ST-segment displacement. 4 The beneficial effects on infarct size correlated well with the reduction of c-jun phosphorylation (À85%; Po0.001 versus control) and of TUNEL-positive cells (À82.1%; Po0.001) in post-ischemic cardiomyocytes. No change in the phosphorylation state of p38 MAPK and ERK in post-ischemic heart was observed in the presence of AS601245 in comparison to the vehicle-treated group. 5 These results demonstrate that blocking the JNK pathway may represent a novel therapeutic approach for treating myocardial ischemia/reperfusion-induced cardiomyocyte death.

We have discovered a new, potent, selective, and orally active oxytocin receptor antagonist, (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2Ј-methyl[1,1Ј-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (compound 1).We report the biochemical, pharmacological, and pharmacokinetic characterization in vitro and in vivo of this compound. Premature birth is a major problem in obstetrics affecting about 10% of all births and being the largest cause of perinatal morbidity and mortality. The impact on society is significant in terms of costs of neonatal intensive care and for the emotional and social stress to the family. The physiopathology of human preterm labor is complex and multifactorial. Preterm increase of uterine activity is a common complication of pregnancy and accounts for many cases of preterm labor. Pharmacological interventions aimed at maintaining uterine quiescence (tocolysis) have been, and are likely to remain, the cornerstone of pharmaceutical management of preterm labor. However, current tocolytic agents (␤-mimetics, magnesium sulfate, calcium channel blockers, or prostaglandin synthesis inhibitors) suffer from a minimal effectiveness and show important fetal and maternal side effects. Therefore, it is obvious that a safe and effective oral treatment delaying spontaneous preterm birth would have tremendous clinical benefits.The peptide hormone oxytocin (OT) is a potent contractor of the human uterus. OT mediates its effect through activation of the G protein-coupled oxytocin receptor (OT-R) that is expressed in myometrial cells. OT-R is coupled to phospholipase C activation, leading to intracellular synthesis of inositol phosphates and mobilization of calcium. In turn, the rise in intracellular calcium concentration promotes a cascade of events, including phosphorylation of myosin, that then acts on actin and induces uterine muscle cell contraction. Before onset of labor and in the term myometrium, the OT-R density Article, publication date, and citation information can be found at

A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.