RESUMEN
Quantum-dot cellular automata (QCA) are a promising nanoscale computing technology that exploits the quantum mechanical tunneling of electrons between quantum dots in a cell and electrostatic interaction between dots in neighboring cells. QCA can achieve higher speed, lower power, and smaller areas than conventional, complementary metal-oxide semiconductor (CMOS) technology. Developing QCA circuits in a logically and physically reversible manner can provide exceptional reductions in energy dissipation. The main challenge is to maintain reversibility down to the physical level. A crucial component of a computer's central processing unit (CPU) is the arithmetic logic unit (ALU), which executes multiple logical and arithmetic functions on the data processed by the CPU. Current QCA ALU designs are either irreversible or logically reversible; however, they lack physical reversibility, a crucial requirement to increase energy efficiency. This paper shows a new multilayer design for a QCA ALU that can carry out 16 different operations and is both logically and physically reversible. The design is based on reversible majority gates, which are the key building blocks. We use QCADesigner-E software to simulate and evaluate energy dissipation. The proposed logically and physically reversible QCA ALU offers an improvement of 88.8% in energy efficiency. Compared to the next most efficient 16-operation QCA ALU, this ALU uses 51% fewer QCA cells and 47% less area.
RESUMEN
Heteroalicyclic carboxamidines were synthesised and evaluated as inhibitors of nitric oxide synthases. (2R)-2-Pyrrolidinecarboxamidine, in particular, was shown to be a highly potent in vitro (IC(50)=0.12 µM) and selective iNOS inhibitor (>100-fold vs both eNOS and nNOS), with probable binding to the key anchoring glutamate residue and co-ordination to the haem iron.
Asunto(s)
Amidinas/síntesis química , Amidinas/farmacología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Hemo/antagonistas & inhibidores , Compuestos Heterocíclicos/síntesis química , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Prolina/análogos & derivados , Amidinas/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Prolina/síntesis química , Prolina/química , Prolina/farmacologíaRESUMEN
A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.
Asunto(s)
Aminas/síntesis química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Éteres/síntesis química , Pirimidinas/síntesis química , Sulfonas/síntesis química , Aminas/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Química Farmacéutica/métodos , Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Modelos Animales de Enfermedad , Diseño de Fármacos , Éteres/farmacología , Humanos , Inflamación , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Enfermedades Neurodegenerativas/tratamiento farmacológico , Pirimidinas/farmacología , Ratas , Sulfonas/farmacologíaRESUMEN
Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.
Asunto(s)
Antivirales/síntesis química , Hepacivirus/efectos de los fármacos , Pirrolidinas/síntesis química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Animales , Antivirales/química , Antivirales/farmacología , Sitios de Unión , Disponibilidad Biológica , Chlorocebus aethiops , Hepacivirus/enzimología , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacología , ARN Polimerasa Dependiente del ARN/química , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Células VeroRESUMEN
Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate. In human cell cultures, compound 32 resulted in suppression of Th2 cytokine responses to allergens, while in vivo intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of 32 of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals.