Synthesis and Structure-Activity Relationships of 8-(Pyrid-3-yl)pyrazolo[1,5-a]-1,3,5-triazines: Potent, Orally Bioavailable Corticotropin Releasing Factor Receptor-1 (CRF1) Antagonists
Bristol-Myers Squibb Co., 311 Pennington-Rocky Hill Road, Hopewell, New Jersey 08540, USA. Journal of Medicinal Chemistry
(Impact Factor: 5.45).
05/2009; 52(9):3084-92. DOI: 10.1021/jm900025h
This report describes the syntheses and structure-activity relationships of 8-(substituted pyridyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. These CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research resulted in the discovery of compound 13-15, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 6.1 +/- 0.6 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 13-15 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 13-15 has been advanced to clinical trials.
Available from: Melanie L Schwandt
- "Recent findings with gabapentin, a medication approved for treatment of seizures and neurogenic pain, support the notion that an ability to suppress alcohol cravings in response to the induction of negative emotions predicts clinical efficacy in alcoholism (Mason et al, 2014, 2009). Here, we carried out a double-blind, placebo-controlled experimental medicine study to evaluate pexacerfont, a selective, orally available and brain-penetrant CRH1 antagonist with potent anti-anxiety activity in experimental animals in the absence of HPA axis effects (Gilligan et al, 2009; Zhou et al, 2012). We enrolled anxious, treatment-seeking alcoholdependent patients, and examined whether pexacerfont would reduce their stress-induced craving for alcohol or neural responses to stressful stimuli presented during functional magnetic resonance imaging (fMRI) sessions. "
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ABSTRACT: Extensive preclinical data implicate corticotropin-releasing hormone (CRH), acting through its CRH1 receptor, in stress- and dependence-induced alcohol seeking. We evaluated pexacerfont, an orally available, brain penetrant CRH1 antagonist for its ability to suppress stress-induced alcohol craving and brain responses in treatment seeking alcohol dependent patients in early abstinence. Fifty-four anxious alcohol dependent participants were admitted to an inpatient unit at the NIH Clinical Center, completed withdrawal treatment, and were enrolled in a double-blind, randomized, placebo controlled study with pexacerfont (300 mg/day for 7 days, followed by 100 mg/day for 23 days). After reaching steady state, participants were assessed for alcohol craving in response to stressful or alcohol-related cues, neuroendocrine responses to these stimuli, and fMRI responses to alcohol-related stimuli or stimuli with positive or negative emotional valence. A separate group of 10 patients received open-label pexacerfont following the same dosing regimen, and had cerebrospinal fluid sampled to estimate central nervous system exposure. Pexacerfont treatment had no effect on alcohol craving, emotional responses, or anxiety. There was no effect of pexacerfont on neural responses to alcohol-related or affective stimuli. These results were obtained despite drug levels in CSF that predict close to 90% central CRH1 receptor occupancy. CRH1 antagonists have been grouped based on their receptor dissociation kinetics, with pexacerfont falling in a category characterized by fast dissociation. Our results may indicate that antagonists with slow offset are required for therapeutic efficacy. Alternatively, the extensive preclinical data on CRH1 antagonism as a mechanism to suppress alcohol seeking may not translate to humans.Neuropsychopharmacology accepted article preview online, 20 November 2014. doi:10.1038/npp.2014.306.
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ABSTRACT: The influence of optical activity on two-wave mixing (TWM) in photorefractive BTO and BSO crystals in the absence of an applied field is studied both theoretically and experimentally. For the conventinal orientations of the grating vector, K  and K⊥, the piezoelectric and photoelastic effects are either zero or negligible. This makes an analytical treatment of the TWM problem possible. We obtain an analytical solution for the coupled wave equations of TWM valid for arbitrary optical activity. This result is of special importance for BTO crystals. In these crystals under the condition of maximum energy transfer (KrD=1, where rD is the Debye radius) neither the approximation of small optical activity nor the one of dominating optical activity is applicable and our analytical solution becomes essential. Our experimental setup uses beams with a trapezoidal overlap that allow us to study the thickness-dependence of the gain in a single measurement. Experimental and theoretical results for a BTO crystal are compared with those for a BSO crystal and are explained in the framework of the model used.
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