4-(1,3-Dimethoxyprop-2-ylamine)-2,7-dimethyl-8-(2,4-dichlorophenyl)-pyrazolo1,5-a-1,3,5-triazine (DMP696) is a highly selective and potent, nonpeptide corticotropin-releasing factor 1 (CRF(1)) ...antagonist. In this study, we measured in vivo CRF(1) receptor occupancy of DMP696 by using ex vivo ligand binding and quantitative autoradiography and explored the relationship of receptor occupancy with plasma and brain exposure and behavioral efficacy. In vitro affinity (IC(50)) of DMP696 to brain CRF(1) receptors measured using the brain section binding autoradiography in this study is similar to that assessed using homogenized cell membrane assays previously. The ex vivo binding assay was validated by demonstrating that potential underestimation of receptor occupancy with this procedure could be minimized by identifying an appropriate in vitro incubation time (40 min) based upon the dissociation kinetics of DMP696. Orally administrated DMP696 dose dependently occupied CRF(1) receptors in the brain, with ~60% occupancy at 3 mg/kg. In the defensive withdrawal test of anxiety, this dose of DMP696 produced approximately 50% reduction in the exit latency. The time course of plasma and brain drug levels paralleled that of receptor occupancy, with peak exposure at 90 min after dosing. The plasma-free concentration of DMP696 corresponding to 50% CRF(1) receptor occupancy (in vivo IC(50), 1.22 nM) was similar to the in vitro IC(50) (~1.0 nM). Brain concentrations of DMP696 were over 150-fold higher than the plasma-free levels. In conclusion, doses of DMP696 occupying over 50% brain CRF(1) receptors are consistent with doses producing anxiolytic efficacy in the defense withdrawal test of anxiety, and the IC(50) value estimated in vivo based on plasma-free drug concentrations is consistent with the in vitro IC(50) value.
Abstract Objectives This multicenter registry aimed to assess the ClearWay™ (CW) perfusion catheter in reduction of thrombus burden and improvement of the coronary flow during percutaneous coronary ...intervention (PCI). Background The presence or development of thrombus during PCI is associated with poor prognosis. Methods The utility of the CW perfusion catheter was assessed in patients who presented with intracoronary thrombus and were subjected to PCI. Data were collected by online survey from 15 US sites. Angiographic assessment of the coronary thrombus burden and the coronary flow after intracoronary infusion of glycoprotein (GP) IIb/IIIa inhibitors via the CW catheter was evaluated at baseline, immediately after infusion, and at the end of the procedure. The cohort included 102 patients; 71.6% presented with ST-elevation myocardial infarction (MI), 21.6% with non-ST-elevation MI, 5.9% with stable angina pectoris, and 2.9% with silent ischemia. The mean cohort age was 59.9 ± 14.5 years and comprised mostly of men (72.5%). Results GP IIb/IIIa inhibitors were infused via the CW catheter on average 1.1 ± 0.3 times, with a mean pressure of 4.2 ± 2.7 atm and a mean infusion time of 55 ± 55 s. Following the infusion, Thrombolysis In Myocardial Infarction (TIMI) flow improved by 1° in 71 patients (69.6%) and by 2° in 51 patients (50%), while visible thrombus was reduced by 52% ( p < 0.001). In the final angiogram, TIMI flow was restored in 90.2% and clearance of a visible thrombus was obtained in 91.8% of the lesions. Conclusion Intracoronary infusion of GP IIb/IIIa inhibitors via the perfusion CW catheter is associated with significant reduction in thrombus burden and with improvement of the coronary flow in patients presenting or developing thrombus burden during PCI.
Corticotropin releasing factor (CRF) is the primary regulator of the hypothalamus-pituitary-adrenal (HPA) axis, coordinating the endocrine, behavioral, and autonomic responses to stress. It has been ...postulated that small molecules that can antagonize the binding of CRF1 to its receptor may serve as a treatment for anxiety-related and/or affective disorders. Members within a series of 3,4-dihydro-1H-pyrido2,3-bpyrazin-2-ones, exemplified by compound 2 (IC50 = 0.70 nM), were found to be very potent antagonists of CRF1. Compound 8w showed high CRF1 receptor binding affinity and was examined further in vivo. The compound was efficacious in a defensive withdrawal model of anxiety in rats and had a long half-life and reasonable oral bioavailability in dog pharmacokinetic studies.
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