The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency.
View Article and Find Full Text PDFHigh-throughput screening highlighted 9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (1) as an active inhibitor of ubiquitin-specific proteases (USPs), a family of hydrolytic enzymes involved in the removal of ubiquitin from protein substrates. The chemical behavior of compound 1 was examined. Moreover, the synthesis and in vitro evaluation of new compounds, analogues of 1, led to the identification of potent and selective inhibitors of the deubiquitinating enzyme USP8.
View Article and Find Full Text PDFCurr Opin Investig Drugs
July 2009
Eli Lilly & Co is developing semagacestat, an inhibitor of the gamma-secretase enzyme. This enzyme is pivotal in the generation of beta-amyloid (A beta), a neurotoxic endogenous peptide believed to be involved in the pathogenesis of Alzheimer's disease (AD). In animals, semagacestat reduced A beta levels in the plasma, CSF and brain; however, studies have not reported on cognitive effect of this compound.
View Article and Find Full Text PDFMuscarinic acetylcholine receptors belong to the G-protein-coupled receptors family. Currently five different receptor subtypes have been identified and cloned. M3 receptor subtypes are coupled to G(q) family proteins and increase phosphatidyl inositol hydrolysis and calcium release from internal stores.
View Article and Find Full Text PDFDrug Discov Today
August 2008
In the scenario of a continuous request for better drugs in shorter times, medicinal chemists must face the challenging task of preparing new patentable molecules, combining high activity and selectivity, drug-likeness and good pharmacokinetic properties. Multiparametric optimization requires a substantial improvement of the efficacy and throughput of the early discovery process, leading to a significant revolution in organic synthesis and chemistry technologies. Chemists are searching for ways to simplify synthetic protocols, for example, by the use of polymer-assisted solution-phase synthesis, microwave-assisted organic synthesis and flow chemistry.
View Article and Find Full Text PDFGamma-secretase modulation holds the promise for the development of a disease-modifying therapy for Alzheimer's disease (AD). This novel concept of manipulating the cleavage specificity of the gamma secretase enzyme by pharmacological means implies that steady state levels of the potentially disease-causing amyloid-beta(1-42) peptide can be lowered without the undesired side effects associated with full inhibition of this aspartyl-type protease. Following on from the initial discovery that certain non-steroidal anti-inflammatory drugs (NSAIDs) exhibit properties characteristic of gamma secretase modulators, this class of compounds has been extensively studied and exploited, leading to the discovery of NSAIDs derivatives endowed with improved potency for the reduction of amyloid-beta(1-42) peptide production.
View Article and Find Full Text PDFSynthesis and biological activity of a novel class of quaternary ammonium salt muscarinic M3 receptor antagonists, showing high selectivity versus the M2 receptor, are described. Selected compounds exhibited potent anticholinergic properties, in isolated guinea-pig trachea, and good functional selectivity for trachea over atria. In vivo, the same compounds potently inhibited acetylcholine-induced bronchoconstriction after intratracheal administration in the guinea pig.
View Article and Find Full Text PDFPharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives.
View Article and Find Full Text PDFAn efficient strategy for the solution-phase parallel synthesis of a library of pyrrole-amides is described. Key reactions include functional homologation of beta-ketoesters with a set of aldehydes followed by oxidation to produce a series of differently substituted 1,4-dicarbonyl compounds. Rapid cyclization using a microwave-assisted Paal-Knorr reaction provided a set of 24 pyrrole esters that were further functionalized through a trimethylaluminum-mediated aminolysis to obtain a larger library of 288 diverse pyrrole-3-amides.
View Article and Find Full Text PDFFlurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit beta-amyloid(1)(-)(42) (Abeta42) secretion, the most toxic component of the senile plaques present in the brain of Alzheimer patients. The use of this NSAID in Alzheimer's disease (AD) is hampered by a significant gastrointestinal toxicity associated with cyclooxygenase (COX) inhibition. New flurbiprofen analogues were synthesized, with the aim of increasing Abeta42 inhibitory potency while removing anti-COX activity.
View Article and Find Full Text PDFChem Commun (Camb)
September 2003
Using a highly efficient solid-phase route a series of fluorescein conjugated peptoid oligomers were synthesised and observed to display remarkable cell penetrating properties, offering the possibility of highly efficient cellular targeting.
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