Multitarget drug discovery projects in CNS diseases: quantitative systems pharmacology as a possible path forward.

Clinical development in brain diseases has one of the lowest success rates in the pharmaceutical industry, and many promising rationally designed single-target R&D projects fail in expensive Phase III trials. By contrast, successful older CNS drugs do have a rich pharmacology. This article will provide arguments suggesting that highly selective single-target drugs are not sufficiently powerful to restore complex neuronal circuit homeostasis. A rationally designed multitarget project can be derisked by dialing in an additional symptomatic treatment effect on top of a disease modification target. Alternatively, we expand upon a hypothetical workflow example using a humanized computer-based quantitative systems pharmacology platform. The hope is that incorporating rationally multipharmacology drug discovery could potentially lead to more impactful polypharmacy drugs.

R278995/CRA0450, a corticotropin-releasing factor (CRF(1)) receptor antagonist modulates REM sleep measures in rats: Implication for therapeutic indication.

Abnormalities in the regulation of the hypothalamic stress hormone corticotropin-releasing factor (CRF) are thought to play a critical role in mood disorders. Consequently, CRF receptor antagonists have been proposed as potential novel therapeutic agents of these conditions. Sleep disturbance is common in depressed patients and changed sleep-wake architecture is considered as potential predictor or surrogate marker of response to treatment. The aim of our study was to characterise the effects of oral administration of the corticotropin-releasing factor CRF(1) receptor antagonist R278995/CRA0450 (3 and 10mg/kg) on sleep-wake organization and electroencephalographic (EEG) components in Sprague-Dawley rats, and to determine whether the changes observed in the sleep-EEG pattern resemble those seen with antidepressants. At 3mg/kg, R278995/CRA0450 produced minor changes in sleep behaviour, while an overall reduction in power spectra was observed during deep slow wave sleep. At 10mg/kg, R278995/CRA0450 consistently reduced rapid eye movement (REM) sleep (-75.4%) and increased the REM sleep onset latency (+67%, 92.1±4.9min for vehicle vs. 153.8±24min for R278995/CRA0450), in the absence of systematic changes in spectral EEG pattern, which are characteristic anti-depressant-like effects. These findings in rats indicate that the corticotropin-releasing factor CRF(1) receptor antagonist R278995/CRA0450 is centrally active under standard conditions as it inhibits REM sleep and promotes wakefulness. The characteristic changes found in the sleep EEG model further support the hypothesis that R278995/CRA0450 could exert a non-sedative, antidepressant-like action.

2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead.

A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.

Anxiolytic- and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450.

1-[8-(2,4-dichlorophenyl)-2-methylquinolin-4-yl]-1,2,3,6-tetrahydropyridine-4-carboxamide benzenesulfonate (R278995/CRA0450) is a newly synthesized corticotropin-releasing factor subtype 1 (CRF(1)) receptor antagonist. In the present study, in vitro and in vivo pharmacological profiles of R278995/CRA0450 were investigated. R278995/CRA0450 showed high affinity for recombinant and native CRF(1) receptors without having affinity for the CRF(2) receptor. R278995/CRA0450 attenuated CRF-induced cyclic AMP formation in AtT-20 cells and CRF-induced forepaw treading in gerbils, indicating that R278995/CRA0450 is an antagonist of the CRF(1) receptor. In addition to CRF(1) receptor antagonism, R278995/CRA0450 showed high affinity for the sigma(1) receptor, and attenuated (+)-SKF10,047-induced head-weaving behavior, suggesting sigma(1) receptor antagonism. R278995/CRA0450 showed dose-dependent in vivo occupancy when assessed by ex vivo receptor binding, indicating good brain penetration. R278995/CRA0450 did not alter spontaneous anxiety when tested in the rat elevated plus maze (up to 3 mg/kg, p.o.) or lick suppression test (up to 10 mg/kg, i.p.). However, potent anxiolytic-like properties were observed in rats subjected to swim stress prior to testing on the elevated plus-maze, indicating activity primarily in tests taxing stress-induced anxiety. R278995/CRA0450 was inactive in mouse tail suspension, rat forced swim and rat differential-reinforcement-of-low-rate 72-s (DRL72), while it showed dose-dependent antidepressant-like effects in the rat learned helplessness paradigm and the olfactory bulbectomy model, demonstrating activity in a subset of animal models of depression associated with subchronic stress exposure. No or only mild effects were seen in tests of locomotor activity, motor coordination and sedation. These results indicate that R278995/CRA0450 is an orally active CRF(1) and sigma(1) receptor antagonist with potent anxiolytic-like and antidepressant-like activities.