Discovery and optimization of imidazo[1,2-a]pyridine inhibitors of insulin-like growth factor-1 receptor (IGF-1R).

The optimization of imidazo[1,2-a]pyridine inhibitors as potent and selective inhibitors of IGF-1R is presented. Further optimization of oral exposure in mice is also discussed. Detailed selectivity, in vitro activity, and in vivo PK profiles of an optimized compound is also highlighted.

In vivo cardiac electrophysiologic effects of a novel diphenylphosphine oxide IKur blocker, (2-Isopropyl-5-methylcyclohexyl) diphenylphosphine oxide, in rat and nonhuman primate.

The voltage-gated potassium channel, Kv1.5, which underlies the ultrarapid delayed rectifier current, I(Kur), is reported to be enriched in human atrium versus ventricle, and has been proposed as a target for novel atrial antiarrhythmic therapy. The administration of the novel I(Kur) blocker (2-isopropyl-5-methyl-cyclohexyl) diphenylphosphine oxide (DPO-1) (0.06, 0.2, and 0.6 mg/kg/min i.v. x 20 min; total doses 1.2, 4.0, and 12.0 mg/kg, respectively) to rat, which exhibits I(Kur) in both atria and ventricle, elicited significant, dose-dependent increases in atrial and ventricular refractory period (9-42%) at all doses tested, with no changes in cardiac rate or indices of cardiac conduction. Plasma levels achieved in rat at the end of the three infusions were 1.1, 4.1, and 7.7 microM. Reverse transcription-polymerase chain reaction analysis of African green monkey atria and ventricle demonstrated an atrial preferential distribution of Kv1.5 transcript. The administration of DPO-1 (1.0, 3.0, and 10.0 mg/kg i.v.; 5-min infusions) to African green monkey elicited significant increases in atrial refractoriness (approximately 15% increase at the 10.0 mg/kg dose), with no change in ventricular refractory period, ECG intervals, heart rate, or blood pressure. Plasma levels of DPO-1 achieved in African green monkey were 0.58, 1.12, and 5.43 microM. The concordance of effect of DPO-1 on myocardial refractoriness with distribution of Kv1.5 in these two species is consistent with the I(Kur) selectivity of DPO-1 in vivo. Moreover, the selective increase in atrial refractoriness in primate supports the concept of I(Kur) blockade as an approach for the development of atrial-specific antiarrhythmic agents.