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  • On the basis of the findings described above


    On the basis of the findings described above, a series of heterotricyclic analogs were designed and synthesized. The human CRF1 receptor binding and antagonist activity data for newly designed heterotricyclic core antagonists 28–33 are described in Table 3. Most of the tricyclic core analogs listed in Table 3 exhibited very potent binding affinity, including analog 33 (X=O) and 31 (X=CH2). Only 31 (X=CH2) exhibited relatively weaker antagonist activity relative to others for its strong binding affinity. The significant reduction of the antagonist activity of 31 relative to the potency of the corresponding NH analog 32 was thought to be caused by the relatively higher lipophilicity of the methylene linker (X=CH2). The most potent antagonist 28 among this series had a 2-chloro-4-methoxyphenyl group as the aryl moiety connected by the linker X=NH. The anxiolytic efficacy of 5, which showed potent antagonist activity in a rat cyclic AMP assay (half maximal effective concentration (EC50)=81 nM, Table 1), was assessed by the Elevated Plus Maze test (Figure 2). Vehicle-treated rats significantly decreased the time spent in open arms (p <0.05) relative to control animals. Pretreatment with cholinesterase inhibitors 5 (10mg/kg, po) significantly increased the spent time in open arms (p=0.050) relative to vehicle-treated animals. Pharmacokinetic data for compound 5 were investigated after its administration in single doses to rats (Table 4). Intravenous administration of 5 to rats (1mg/kg, n=4) resulted in detectable plasma levels (half-life (T1/2)=1.7h), whereas oral administration of 5 to rats (10mg/kg, n=4) resulted in a T1/2 of 3.4h. The area under the curve (AUC) value of 5 was 96ng·h/mL after intravenous administration versus 153ng·h/mL after oral administration. The steady state volume of distribution (Vss) was calculated to be 14423mL/kg, indicating that this compound showed good distribution in tissues. Systemic clearance (CL) was 186ml/min/kg, indicating that this compound was susceptible to being metabolized. The Cmax value after oral dosing was 27.4ng/mL, whereas the Tmax value was 4.0h. The bioavailability of 5 was 16%. Kp value (brain content of 5/plasma concentration of 5) was 6.2 (1.0h after oral dosing).
    Conclusion A series of bicyclic core antagonists, pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidine-5,7-diamines, imidazo[1,2-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines were designed, synthesized and evaluated as CRF1 antagonists. Some of the pyrazolo[1,5-a]pyrimidines 3, 5, 6 and 19 showed strong in vitro activities. Among them, 5 showed oral efficacy at 10mg/kg in the Elevated Plus Maze test in rats. Further design and synthesis for structural diversity led us to discover a series of tricyclic core antagonists, pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidines. Despite their very strong in vitro activities, they did not show oral efficacy because of the presumed pharmacokinetic problems.
    Introduction Classical fear conditioning is the process by which a previously neutral stimulus comes to evoke fear following its repeated pairing with an aversive unconditioned stimulus. The inability to learn these fear contingencies results in unpredictability of the aversive event and consequently in maladaptive fear, reflected in enhanced contextual fear (Baas et al., 2008, Grillon, 2002). Literature suggests that this type of associative learning deficit plays a crucial role in the development of several anxiety disorders, including panic disorder (Lissek et al., 2009). The serotonin system is involved in fear regulation (Burghardt et al., 2004, Grillon et al., 2007a). In addition, serotonin has been implicated in both the pathology and the treatment of panic disorder. First, selective serotonin re-uptake inhibitors (SSRIs), acting on the serotonin transporter, are medication of choice for panic disorders (Andrews and Hunt, 1998, Romano et al., 2004). Further, panic disorder has been associated with a polymorphism in the serotonin transporter gene (SLC6A4) (Strug et al., 2010) increased serotonin turnover (Esler et al., 2007) and both decreased and increased serotonin transporter availability (Maron et al., 2004, Maron et al., 2011).