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The SAR of brain penetration for a series of heteroaryl piperazinyl- and piperadinyl-urea fatty acid amide hydrolase (FAAH) inhibitors is described. Brain/plasma (B/P) ratios ranging from >4:1 to as low as 0.02:1 were obtained through relatively simple structural changes to various regions of the heteroaryl urea scaffold. It was not possible to predict the degree of central nervous system (CNS) penetration from the volumes of distribution ( V d ) obtained from pharmacokinetic (PK) experiments as very high V d s did not correlate with high B/P ratios. Similarly, calculated topological polar surface areas (TPSAs) did not consistently correlate with the degree of brain penetration. The lowest B/P ratios were observed for those compounds that were significantly ionized at physiological pH. However, as this class of compounds inhibits the FAAH enzyme through covalent modification, low B/P ratios did not preclude effective central target engagement. [ABSTRACT FROM AUTHOR]

Abstract: A series of 1-aryl-2-(((6-aryl)pyrimidin-4-yl)amino)ethanols have been found to be competitive inhibitors of fatty acid amide hydrolase (FAAH). One member of this class, JNJ-40413269, was found to have excellent pharmacokinetic properties, demonstrated robust central target engagement, and was efficacious in a rat model of neuropathic pain. [Copyright &y& Elsevier]

Abstract: A series of mechanism based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with spirocyclic diamine cores is described. A potent member of this class, (37), was found to inhibit FAAH centrally, elevate the brain levels of three fatty acid ethanolamides [FAAs: anandamide (AEA), oleoyl ethanolamide (OEA) and palmitoyl ethanolamide (PEA)], and was moderately efficacious in a rat model of neuropathic pain. [Copyright &y& Elsevier]

Abstract: The structure–activity relationships for a series of heteroaryl urea inhibitors of fatty acid amide hydrolase (FAAH) are described. Members of this class of inhibitors have been shown to inactivate FAAH by covalent modification of an active site serine with subsequent release of an aromatic amine from the urea electrophile. Systematic Ames II testing guided the optimization of urea substituents by defining the structure–mutagenicity relationships for the released aromatic amine metabolites. Potent FAAH inhibitors were identified having heteroaryl amine leaving groups that were non-mutagenic in the Ames II assay. [Copyright &y& Elsevier]

Objectives: Single-incision laparoscopic cholecystectomy (SILC) may be associated with less pain, shorter hospital stay and better cosmetic results than multiport laparoscopic cholecystectomy (MLC). Advocates suggest that patients prefer SILC, although research directly addressing the question of patient preferences is limited. This study aimed to assess patient preferences using currently available evidence. Methods: Patients awaiting elective cholecystectomy were shown a series of postoperative images taken after SILC or MLC and asked which procedure this led them to prefer. This was repeated after patients had completed a questionnaire constructed using published objective data comparing patient-reported outcomes of SILC and MLC. Results: The study was completed by 113 consecutive patients. After their initial viewing of the images, 16% of subjects preferred MLC. Younger age, lower body mass index and female sex were associated with choosing SILC. After completing the questionnaire, 88% of patients preferred MLC ( P < 0.001). Patients ranked the level of risk for complications and postoperative pain above cosmetic results in determining their choice of procedure. Conclusions: Patients' initial preference when presented with cosmetic appearance was for SILC. When contemporary outcome data were included, the majority chose MLC. This underlines the need to fully inform patients during the consent process and indicates that patient views of SILC may differ from the views of those introducing the technology. [ABSTRACT FROM AUTHOR]

Abstract: Rational development of nanotechnology through electrochemistry requires a thorough understanding of electronic, magnetic, as well as atomic level structural details of surfaces under electrochemical environments. Using first principles density functional theory (DFT), we investigated these features in the mechanism of metallizing a self-assembled monolayer of organic molecules attached to a metallic surface with Pd. We focused our studies on the √3×√3 structure of the 4-mercaptopyridine (4MP)-SAM adsorbed on Au(111), first elucidating the nature of metal–SAM interactions, and then providing a general mechanism to explain the initial stages of SAM-metallization with Pd. Calculations support that SAM relaxation permits facile aggregation of metal atoms to form a hanging metal overlayer. The calculated electronic structures of possible overlayers interacting with the supporting SAM are compared to experiment. [ABSTRACT FROM AUTHOR]

Emerging techniques in deep learning have created exciting opportunities for next-generation electrochemical technologies. While deep learning has been revolutionizing many research fields, strategies for its implementation for electrocatalysis remain nascent. This Opinion calls on the electrocatalysis community to join together and introduce a paradigm shift by establishing standards for reporting and sharing data from electrocatalysis investigations. We speculate on a possible future where crowd-sourced and standardized data from experimental and computational researchers can be analyzed collectively to better understand fundamental electrochemistry, yielding unprecedented insights for the development of new electrocatalysts. We identify key barriers to realizing this opportunity and how they might be overcome. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis and biological activity of a new series of 2-aryloxymethylmorpholine histamine H3 antagonists is described. The new compounds are high affinity histamine H3 ligands that penetrate the CNS and occupy the histamine H3 receptor in rat brain. [Copyright &y& Elsevier]

Abstract: A series of thiadiazolopiperazinyl aryl urea fatty acid amide hydrolase (FAAH) inhibitors is described. The molecules were found to inhibit the enzyme by acting as mechanism-based substrates, forming a covalent bond with Ser241. SAR and PK properties are presented. [Copyright &y& Elsevier]

Abstract: Currently, the only clinically effective treatment for Alzheimer’s disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have limited efficacy in that they only treat the symptoms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single molecule having the actions of both an AChE inhibitor and histamine H3 receptor antagonist. Both histamine H3 receptor antagonists and AChE inhibitors improve and augment cholinergic neurotransmission in the cortex. However, whereas an AChE inhibitor will impart its effect everywhere, a histamine H3 antagonist will raise acetylcholine levels mostly in the brain as its mode of action will primarily be on the central nervous system. Therefore, the combination of both activities in a single molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting compound may offer the desired therapeutic effect with fewer unpleasant side effects [CNS Drugs 2004, 18, 827]. Further, recent studies indicate the peripheral anionic site (PAS) of AChE interacts with the β-amyloid (βA) peptide. Consequently, a molecule capable of disrupting this interaction may have a significant impact on the production of or the aggregation of βA. This may result in slowing down the progression of the disease rather than only treating the symptoms as current therapies do. Here, we detail how the use of the available crystal structure information, pharmacophore modeling and docking (automated, manual, classical, and QM/MM) lead to the identification of an AChE inhibitor–histamine H3 receptor antagonist. Further, based on our models we speculate that this dual-acting compound may interact with the PAS. Such a dual-acting compound may be able to affect the pathology of AD in addition to providing symptomatic relief. [Copyright &y& Elsevier]

Abstract: A series of tetrahydroisoquinolines acting as dual serotonin transporter inhibitor/histamine H3 antagonists is described. The introduction of polar aromatic spacers as part of the histamine H3 pharmacophore was explored. A convergent synthesis of the final products allowing late stage introduction of the aromatic side chain was developed. In vitro and in vivo data are discussed. [Copyright &y& Elsevier]

Abstract: A series of novel and potent 6-heteroaryl-pyrrolidino-tetrahydroisoquinolines with dual histamine H3 antagonist/serotonin transporter inhibitor activity is described. In vitro and in vivo data are discussed. [Copyright &y& Elsevier]

Abstract: A series of novel tetrahydronaphthyridine-based histamine H3 ligands that have serotonin reuptake transporter inhibitor activity is described. The 1,2,3,4-tetrahydro-2,6-naphthyridine scaffold is assembled via the addition of a nitrostyrene to a metalated pyridine followed by reduction and cyclization to form the naphthyridine. In vitro biological data for these novel compounds are discussed. [Copyright &y& Elsevier]

Abstract: A series of novel 4-aryl-1,2,3,4-tetrahydroisoquinoline-based histamine H3 ligands that also have serotonin reuptake transporter inhibitor activity is described. The synthesis, in vitro biological data, and select pharmacokinetic data for these novel compounds are discussed. [Copyright &y& Elsevier]

Iodine in methanol has been found to be an effective catalyst system for the cleavage of alkoxymethyl ethers. This catalyst system is particularly useful for the selective removal of ortho-methoxymethyl- and ortho-(4-methoxybenzyl) ethers in the presence of their para-counterparts. Further investigation of various metal salts in methanol for their ability to cleave alkoxymethyl ethers revealed high-valent salts as effective catalysts, presumably through the release of small quantities of HCl. [Copyright &y& Elsevier]

A series of mechanism-based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with fused bicyclic diamine cores is described. In contrast to compounds built around a piperazine core, most of the fused bicyclic diamine bearing analogs prepared exhibited greater potency against rFAAH than the human enzyme. Several compounds equipotent against both species were identified and profiled in vivo. [ABSTRACT FROM AUTHOR]

We have used Kohn-Sham density functional theory with atomistic thermodynamics to identify various forms of N-doped graphene basal planes and nanoribbons that are thermodynamically relevant for CO 2 electroreductions. Using our computational results, we derive phase diagrams for different nanocarbon structures, and we report which structures are suitable for hydrogen transfers to CO 2 with low overpotentials. With the incorporation of N atoms, standard reduction potentials resulting in hydrogenated surfaces become less negative, and this effectively opens pathways for hydrogen atom shuttling to CO 2 with reversibly hydrogenating nanocarbon catalysts. Of all morphologies considered, N-doped zigzag nanocarbon edges are most favorable for energetically efficient CO 2 electroreductions. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis and biological activity of a new series of piperazine and diazepane amides is described. The new compounds are high affinity histamine H3 ligands and serotonin reuptake inhibitors. [Copyright &y& Elsevier]

5-Lipoxygenase activating protein (FLAP) plays a critical role in the metabolism of arachidonic acid to leukotriene A4, the precursor to the potent pro-inflammatory mediators leukotriene B4 and leukotriene C4. Studies with small molecule inhibitors of FLAP have led to the discovery of a drug binding pocket on the protein surface, and several pharmaceutical companies have developed compounds and performed clinical trials. Crystallographic studies and mutational analyses have contributed to a general understanding of compound binding modes. During our own efforts, we identified two unique chemical series. One series demonstrated strong inhibition of human FLAP but differential pharmacology across species and was completely inactive in assays with mouse or rat FLAP. The other series was active across rodent FLAP, as well as human and dog FLAP. Comparison of rodent and human FLAP amino acid sequences together with an analysis of a published crystal structure led to the identification of amino acid residue 24 in the floor of the putative binding pocket as a likely candidate for the observed speciation. On that basis, we tested compounds for binding to human G24A and mouse A24G FLAP mutant variants and compared the data to that generated for wild type human and mouse FLAP. These studies confirmed that a single amino acid mutation was sufficient to reverse the speciation observed in wild type FLAP. In addition, a PK/PD method was established in canines to enable preclinical profiling of mouse-inactive compounds. [ABSTRACT FROM AUTHOR]

Sodium borohydride (NaBH 4 ) reacts with carbon dioxide (CO 2 ) and bicarbonate (HCO 3 − ) in aqueous solution to produce formate (HCO 2 − ). Isotopic labeling experiments verified the product identity and illustrated that the carbon in the product originated from CO 2 /HCO 3 − . The addition of CO 2 to borohydride resulted in formate production in isopropanol as well. Accurate first-principles quantum chemistry was used to examine reaction energies and the hydricities of various borohydrides in aqueous solution. CO 2 reduction is proposed to proceed through hydride transfer from BH 4 − or from BH 4− n (OH) n − ( n = 0–3) to CO 2 and bicarbonate. The reaction energies were found to be competitive with those for hydrolysis of borohydride. These findings lay the foundation for the further development of systems for the catalytic conversion of CO 2 and bicarbonate into fuels via hydride transfers in water. [ABSTRACT FROM AUTHOR]

Abstract: The pre-clinical characterization of novel aryloxypyridine amides that are histamine H3 receptor antagonists is described. These compounds are high affinity histamine H3 ligands that penetrate the CNS and occupy the histamine H3 receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates. [Copyright &y& Elsevier]