Pharmacological evaluation of novel bioisosteres of an adamantanyl benzamide P2X7 receptor antagonist

Adamantanyl benzamide 1 was identified as a potent P2X7R antagonist but failed to progress further due to poor metabolic stability. We describe the synthesis and SAR of a series of bioisosteres of benzamide 1 to explore improvements in the pharmacological properties of this lead. Initial efforts investigated a series of heteroaromatic bioisosteres, which demonstrated improved physicochemical properties but reduced P2X7R antagonism. Installation of bioisosteric fluorine on the adamantane bridgeheads was well tolerated and led to a series of bioisosteres with improved physicochemical properties and metabolic stability. Trifluorinated benzamide 34 demonstrated optimal physicochemical parameters, superior metabolic stability (ten times longer than lead benzamide 1), and an improved physicokinetic profile and proved effective in the presence of several known P2X7R polymorphisms

Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug

As human life expectancy has improved rapidly in industrialized societies, age-related cognitive impairment presents an increasing challenge. Targeting histopathological processes that correlate with age-related cognitive declines, such as neuroinflammation, low levels of neurogenesis, disrupted blood-brain barrier and altered neuronal activity, might lead to structural and functional rejuvenation of the aged brain. Here we show that a 6-week treatment of young (4 months) and old (20 months) rats with montelukast, a marketed anti-asthmatic drug antagonizing leukotriene receptors, reduces neuroinflammation, elevates hippocampal neurogenesis and improves learning and memory in old animals. By using gene knockdown and knockout approaches, we demonstrate that the effect is mediated through inhibition of the GPR17 receptor. This work illustrates that inhibition of leukotriene receptor signalling might represent a safe and druggable target to restore cognitive functions in old individuals and paves the way for future clinical translation of leukotriene receptor inhibition for the treatment of dementias

Identification of the allosteric P2X7 receptor antagonist [11C]SMW139 as a PET tracer of microglial activation

The P2X7 receptor plays a significant role in microglial activation, and as a potential drug target, the P2X7 receptor is also an interesting target in positron emission tomography. The current study aimed at the development and evaluation of a potent tracer targeting the P2X7 receptor, to which end four adamantanyl benzamide analogues with high affinity for the human P2X7 receptor were labelled with carbon-11. All four analogues could be obtained in excellent radiochemical yield and high radiochemical purity and molar activity, and all analogues entered the rat brain. [11C]SMW139 showed the highest metabolic stability in rat plasma, and showed high binding to the hP2X7 receptor in vivo in a hP2X7 receptor overexpressing rat model. Although no significant difference in binding of [11C]SMW139 was observed between post mortem brain tissue of Alzheimer's disease patients and that of healthy controls in in vitro autoradiography experiments, [11C]SMW139 could be a promising tracer for P2X7 receptor imaging using positron emission tomography, due to high receptor binding in vivo in the hP2X7 receptor overexpressing rat model. However, further investigation of both P2X7 receptor expression and binding of [11C]SMW139 in other neurological diseases involving microglial activation is warranted

Modeling combustion under engine combustion network Spray A conditions with multiple injections using the transported probability density function method

In this study, numerical simulations of an n-dodecane spray flame - known as Spray A - with multiple injections (0.5 ms injection/0.5 ms dwell/0.5 ms injection) have been carried out using the transported probability density function method in the Reynolds-averaged Navier-Stokes framework. In terms of the methodology employed, the transported probability density function method can handle the multiple-injections case without any modification because the model does not assume that thermodynamical states lie on a low-dimensional manifold such as the mixture fraction manifold, as is the case for many other turbulent combustion models, for example, the representative interactive flamelet model and the conditional moment closure model. Simulation results have been compared with recent experimental data in terms of inert and reactive jet tip penetration and vapor boundary (from schlieren imaging), ignition delay and flame base location of the first and second fuel injection, spatial distribution of formaldehyde (CH2O) and polyaromatic hydrocarbon (from 355-nm planar-laser-induced fluorescence). Particular attention has been paid to the ignition behavior of the second fuel injection. The timing and progression of the first- and second-stage ignition events are qualitatively well reproduced by the model. Simulation results have been further analyzed to assess the validity of the beta-function as the presumed shape of the mixture fraction probability density function, which is typically employed in mixture fraction-based models. The beta-function probability density function was found to provide a good approximation throughout the jet region apart from a brief period of around 100 μs when the second fuel stream encounters the pre-existing fuel-air mixture from the first fuel injection. Overall, it is shown that the transported probability density function model is able to capture the main features related to auto-ignition involved with multiple injections, and simulation results can be used to assess some of the underlying assumptions invoked by other models