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Publications (3)9.69 Total impact

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    ABSTRACT: Abnormal accumulation of neurotoxic beta-amyloid peptides (Aβ) is a key factor in the development of Alzheimer's disease (AD) and strategies to reduce Aβ production constitute an active field of research for the development of novel therapeutic agents for the treatment of AD. In particular, β-secretase-1 (BACE-1) has been a prime target for modulating Aβ production although obtaining drug-like BACE-1 inhibitors has proven to be highly challenging. Here we report the isolation and biochemical characterization of a marine natural product, the prenylated hydroxybenzoic acid 1, with BACE-1 inhibitory activity and ability to decrease Aβ production in cell-based assays. Synthesis and biological activity of a number of new synthetic analogues are also reported, as well as initial structure-activity relationship (SAR) analysis on this chemical family. Hence, these compounds constitute novel scaffolds from which more potent and selective BACE-1 inhibitors could be designed as potential therapeutic agents for the treatment of Alzheimer's disease.
    Medicinal Chemistry Communication 01/2014; 5(4):474. · 2.63 Impact Factor
  • Javier López-Ogalla, Gonzalo Saiz, Francisco E. Palomo
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    ABSTRACT: An efficient synthetic process for the natural product of marine origin, collismycin type A, a potent neuroprotector agent, has been developed. This new synthetic route avoids chromatographic steps, implies an improvement cost, and provides easy access to large scale.
    Organic Process Research & Development 01/2013; 17(1):120–126. · 2.55 Impact Factor
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    ABSTRACT: Enhancement of adiponectin level has been shown to have beneficial effects, including antiobesity, antidiabetic, and hepatoprotective effects. This evidence supports the therapeutic utility of adiponectin in complicated obesity. The present study characterized the in vivo effects of sustained adiponectin release by NP-1, a new class of thiazol derivative that increases adiponectin levels. Acute administration of NP-1 reduced feeding, increased plasma adiponectin, and improved insulin sensitivity without inducing malaise, as revealed by conditioned taste aversion studies. Short-term (7 days) treatment with NP-1 also reduced feeding and body weight gain and increased phosphorylation of AMPK in muscle, a main intracellular effector of adiponectin. NP-1 was also evaluated in diet-induced obesity, and adult male Wistar rats were fed two different types of diet: a standard high-carbohydrate/low-fat diet (SD) and a high-fat diet (HFD). Once obesity was established, animals were treated daily with NP-1 (5 mg/kg) for 14 consecutive days. Chronic NP-1 induced body weight loss and reduction of food intake and resulted in both a marked decrease in liver steatosis and an improvement of biochemical indexes of liver damage in HFD-fed rats. However, a marked induction of tolerance in adiponectin gene transcription and release was observed after chronic NP-1 with respect to the acute actions of this drug. The present results support the role of adiponectin signaling in diet-induced obesity and set in place a potential use of compounds able to induce adiponectin release for the treatment of obesity and nonalcoholic fatty liver, with the limits imposed by the induction of pharmacological tolerance.
    AJP Endocrinology and Metabolism 01/2012; 302(7):E817-30. · 4.51 Impact Factor