Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (NSAID) use; and opioids' addiction are unresolved challenges. We developed SRP-001, a non-opioid and non-hepatotoxic small molecule that, unlike ApAP, does not produce the hepatotoxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI) and preserves hepatic tight junction integrity at high doses.
View Article and Find Full Text PDFThe safe and effective management of pain is a critical healthcare and societal need. The potential for misuse and addiction associated with opioids, nephrotoxicity, and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (NSAID) use, as well as acute liver injury from paracetamol (ApAP) overdose, are unresolved challenges. To address them, we developed a non-opioid and non-hepatotoxic small molecule, SRP-001.
View Article and Find Full Text PDFAlthough acetaminophen (ApAP) is one of the most commonly used medicines worldwide, hepatotoxicity is a risk with overdose or in patients with compromised liver function. ApAP overdose is the most common cause of acute fulminant hepatic failure. Oxidation of ApAP to N-acetyl-p-benzoquinone imine (NAPQI) is the mechanism for hepatotoxicity.
View Article and Find Full Text PDFA variety of aminated bipyridines and bipyridine sultams are prepared by intramolecular radical [1,5]- and [1,6]- substitutions, using a sulfonamide as a linker to connect the pyridyl radical to the pyridine under attack. For the cases studied, different regiochemistries are observed depending on the initial position of the sulfonamide linker.
View Article and Find Full Text PDFIn colorectal carcinoma patients, distant metastatic disease is present at initial diagnosis in nearly 25% of them. The majority of patients with metastatic colorectal carcinoma have incurable disease; therefore, new therapies are needed. Agents derived from medicinal plants have already demonstrated therapeutic activities in human cancer cells.
View Article and Find Full Text PDFIn this review we highlight the most modern trends in the prodrug strategy. In drug research and development, the prodrug concept has found a number of useful applications. Selected examples of this approach are provided in this paper and they are classified according to the aim of their design.
View Article and Find Full Text PDFAzonia aromatic heterocycles are an important subclass of aza-heterocyles as they are the structural motif of relevant cationic alkaloids, and they have a wide range of potential applications such as bioactive compounds and organic materials. In this Synopsis, recent and novel approaches to their synthesis are surveyed, with particular emphasis on ring-closing metathesis reactions and annulation reactions based on C-H activation.
View Article and Find Full Text PDFThe synthesis of the new radiotracer precursor 4-Br-NITTP and the radiolabeling of the new tracer 1-(4-bromo-2-nitroimidazol-1-yl)-3-[(18)F]fluoropropan-2-ol (4-Br-[(18)F]FMISO) is reported. The cyclic voltammetry behaviour, neuronal cell toxicity, transport through the brain endothelial cell monolayer, in vivo PET imaging and preliminary calculations of the tracer uptake for a rodent model of stroke were studied for the new compound and the results were compared to those obtained with [(18)F]FMISO, the current gold standard PET hypoxia tracer. The new PET brain hypoxia tracer is more easily reduced, has higher CLogP than [(18)F]FMISO and it diffuses more rapidly through brain endothelial cells.
View Article and Find Full Text PDFCondensed polycyclic heteroaromatic cations bearing a bridgehead nitrogen with pyridazino[1',6':1,2]pyrido[3,4-b]indolinium and pyridazino[1,6-a]benzimidazolium structures were assayed as inhibitors of LPS-induced TNF-α production by THP-1 cells. The hit compound 1e, which had the best IC50 value (4.49 μM) and low toxicity, was further assayed on human PMBCs (IC50 3.
View Article and Find Full Text PDFN-(4-[(18)F]-Fluoropyridin-2-yl)-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-carboxamides were prepared by labeling their 4-nitropyridin-2-yl precursors through nitro substitution by the (18)F anion. In vitro and in vivo tests showed that the cyclohexanecarboxamide derivative is a reversible, selective and high affinity 5-HT1A receptor antagonist (IC50 = 0.29 nM, ki = 0.
View Article and Find Full Text PDFTwo total syntheses of the indolo[2,3-a]quinolizinium cation have been accomplished through the application of two ring-closing metathesis reactions to form the pyridinium ring. One of these approaches provides the tetracyclic cation in only five steps from commercially available harmane. Fluorescence-based thermal denaturation experiments, as well as spectrofluorimetric titration, circular dichroism measurements, and theoretical simulations, showed a consistent DNA-binding capacity by intercalation with a marked preference for AT-rich sequences.
View Article and Find Full Text PDFA series of novel thienopyrimidin-4-amines have been synthesized and evaluated as phosphodiesterase (PDE) inhibitors. A rationale for the observed selectivity against PDE7 has been obtained from molecular modelling studies on the most active compounds.
View Article and Find Full Text PDFA three-step synthetic pathway has been employed to synthesize a small library of 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethanone and 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethane-1,2-dione derivatives that have been screened in [(3)H]ifenprodil competition binding assay. Some compounds exhibited significant binding affinity at nanomolar concentration, the most active being ligand 35 (IC50=5.5nM).
View Article and Find Full Text PDFCharged chromophores based on heteroaromatic cations were prepared by reaction of alkylazinium salts with N-heteroarylstannanes under Stille conditions. This approach provides easy access to potential single donor D-A(+) chromophores in which the acceptor moiety A(+) is the pyridinium cation and the donors are different π-excessive N-heterocycles. The β hyperpolarizabilities were measured in hyper-Rayleigh scattering experiments and the experimental data are supported by a theoretical analysis that combines a variety of computational procedures, including density functional theory and correlated Hartree-Fock-based methods.
View Article and Find Full Text PDFThe reaction of alkyl tosylmethyl isocyanides and 2-bromobenzyl bromides in the presence of t-BuLi gives rise to a cascade reaction to give unexpected 2-substituted 2,3-dihydro-1H-indenimines which, upon treatment with t-BuOK, rearrange to 2-vinylbenzonitriles in high overall yields. This simple procedure represents a new approach to the synthesis of aromatic nitriles via isocyanide-cyanide interconversion.
View Article and Find Full Text PDFSeveral indole derivatives, that were highly potent ligands of GluN2B-subunit-containing N-methyl-D-aspartate (NMDA) receptor, also demonstrated antioxidant properties in ABTS method. In particular, the 2-(4-benzylpiperidin-1-yl)-1-(5-hydroxy-1H-indol-3-yl)ethanone (1) proved to be a dual-effective neuroprotective agent. With the aim to increase the antioxidant properties we added a catechol moiety onto piperidine moiety.
View Article and Find Full Text PDFThe latest scientific findings concerning PDE7 and PDE4 inhibition suggest that selective small-molecule inhibitors of both enzymes could provide a novel approach to treat a variety of immunological diseases. In this context, we describe a new series of quinazoline derivatives from quinazolin-4-thiones which include a substituted biphenyl fragment. Some of these compounds show inhibitory potencies at sub-micromolar levels against the catalytic domain of PDE7.
View Article and Find Full Text PDFThe reaction of bromo substituted pyrido[3',2':4,5]pyrrolo-[1,2-c]pyrimidine and pyrimido[1,6-a]indole methyl carboxylates with primary amines is described. The expected amide formation occurs but it is followed by an unexpected cascade process involving attack of the amine to the pyrimidine ring, opening of the pyrimidine ring, loss of the bromine substituent and competitive cyclizations to afford unusual imidazolidene substituted indoles and azaindoles.
View Article and Find Full Text PDFThe synthesis of 9,9'-[1,2-ethanediylbis(oxymethylene)]bis-2-amino-1,9-dihydro-6H-purin-6-one, a minor impurity of acyclovir, is described. Starting with commercial N-(9-acetyl-6-oxo-1H-purin-2-yl)acetamide, the process uses an acid catalysed phase transfer catalysis (PTC) process to produce the selective alkylation at the 9 position of the guanine ring.
View Article and Find Full Text PDFPlatelet-activating factor (PAF) accumulates during cerebral ischemia, and inhibition of this process plays a critical role in neuronal survival. Recently, we demonstrated that LAU-0901, a novel PAF receptor antagonist, is neuroprotective in experimental stroke. We used magnetic resonance imaging in conjunction with behavior and immunohistopathology to expand our understanding of this novel therapeutic approach.
View Article and Find Full Text PDFWe report new examples of a series of losartan-hydrocaffeic hybrids that bear novel ester, amide and amine linkers. These compounds were made by linking hydrocaffeic acid to the side chain of losartan at the C-5 position of the imidazole ring through different strategies. Experiments performed in cultured cells demonstrate that these new hybrids retain the ability to block the angiotensin II effect and have increased antioxidant ability.
View Article and Find Full Text PDFHeteroaromatic cations reacted with N-heteroarylacetylenes under Sonogashira conditions to allow easy access to potential single donor D-π-A(+) and V-shaped D-π-A(+)-π-D chromophores, where the acceptor moiety A is the π-deficient pyridinium cation and the donor moiety is represented by different π-excessive N-heterocycles. The β hyperpolarizabilities were measured using hyper-Rayleigh scattering experiments and the experimental data are supported by a theoretical analysis that combines a variety of computational procedures, including Density Functional Theory (DFT) and correlated Hartree-Fock-based methods (RCIS(D)).
View Article and Find Full Text PDFTris(trimethylsilyl)silane and azobis(cyclohexanenitrile) promoted the easy intramolecular arylation of aryl bromopyridine carbamates through a radical [1,6] ipso substitution process. These substrates showed a preference for this type of reaction over the alternative [1,7] addition. The results were rationalized by making use of quantum mechanical calculations and computer graphics.
View Article and Find Full Text PDFWe report the first examples of a new series of antioxidant-sartan hybrids (AO-sartans), which were made by adding an antioxidant fragment to the hydroxymethyl side chain of losartan. Experiments performed in cultured cells demonstrate that these new hybrids retain the ability to block the angiotensin II effect with increased antioxidant ability. In hypertensive rats, these compounds show properties that suggest they may be more useful than losartan for controlling hypertension and preventing hypertension-induced cardiovascular damage.
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