Novel Selective Inhibitors of Neutral Endopeptidase for the Treatment of Female Sexual Arousal Disorder. Synthesis and Activity of Functionalized Glutaramides

The copper(I)-catalyzed 1,2,3-triazole-forming reaction between azides and terminal alkynes has become the gold standard of click chemistry due to its reliability, specificity, and biocompatibility. Applications of click chemistry are increasingly found in all aspects of drug discovery; they range from lead finding through combinatorial chemistry and target-templated in vitro chemistry, to proteomics and DNA research by using bioconjugation reactions. The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen-bonding and dipole interactions. The present review will focus mainly on the recent literature for applications of this reaction in the field of medicinal chemistry, in particular on use of the 1,2,3-triazole moiety as pharmacophore.

show abstract

“…[130] One of the compounds (65) that contains the 1,2,3-triazole exhibited appreciable potency (82 nm) against NEP.…”

Section: Antifungal and Antibacterialsmentioning

confidence: 99%

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

Agalave

Maujan

Pore

2011

Chemistry An Asian Journal

1,167

508

View full text Add to dashboard Cite

show abstract

“…This fixed combination is in currently in Phase 3 clinical trials for chronic heart failure. Discovery of carboxylate containing NEP inhibitors (16) and (17) have also been reported and are being developed as medicines for treatment of female sexual arousal disorder [37,38]. Their discovery was based on candoxatrilat as a start point.…”

Section: Recent Advances In Medicinal Chemistry Of Nep Inhibitorsmentioning

confidence: 99%

Recent Advances in Discovery and Development of Medicines for the Treatment of Secretory Diarrhea in the Developing World

Marquess

2011

Topics in Medicinal Chemistry

View full text Add to dashboard Cite

Secretory diarrhea remains a global health challenge in the developing and developed countries. Secretory or infectious diarrhea is caused by infection of the gastrointestinal tract with a bacterial, viral, or parasitic pathogen. Acute diarrheal diseases have a major impact on morbidity and mortality across the world, with as many as four billion cases occurring annually. Diarrheal disease is responsible for the approximately 1.7 million deaths in children under 5 years old annually. Preventative healthcare measures include safe and effective vaccines and improved water, sanitation, hygiene systems, and nutritional practices. Treatment options in developing countries are usually supportive, replacing intestinal fluid losses with oral rehydration solution (ORS). Oral rehydration therapy (ORT) is well accepted as the most effective treatment for rehydration of children with acute diarrhea and is recommended by the World Health Organization for the prevention and management of dehydration. Its use has resulted in a significant reduction in diarrhea-related mortality. ORT has been recently complemented by zinc supplementation therapy. Rehydration has little effect on stool volume or frequency; therefore, the World Health Organization has recommended that anti-secretory drug treatment be added to rehydration therapy as long as the treatment has proven safe and efficacious in the pediatric population. In the developing countries, Hydrasec™ (racecadotril) is the most widely used antisecretory antidiarrheal, particularly in children. This review focuses on recent advances in the discovery and development of medicines and pharmacological mechanisms that modulate the secretory component of diarrhea that could be efficacious in the treatment of infectious diarrhea in the developing countries, particularly in the pediatric population.

show abstract

“…NEP in endometrial stromal cells has been proposed as a helpful tool in diagnosis of endometriosis (Groisman and Meir 2003). The involvement of the enzyme in the hydrolysis of the vasoactive intestinal peptide (VIP) was the basis for a recent study that resulted in the development of very selective inhibitors for NEP, which can be used in the treatment of female sexual arousal disorder (Pryde et al 2006). It was suggested that, by selective NEP inhibition, VIP levels could increase thereby enhance VIP-induced increase in vaginal blood flow (Pryde et al 2006).…”

Section: Neprilysin Carboxydipeptidase Specificity Studies and Improvmentioning

confidence: 99%

“…The involvement of the enzyme in the hydrolysis of the vasoactive intestinal peptide (VIP) was the basis for a recent study that resulted in the development of very selective inhibitors for NEP, which can be used in the treatment of female sexual arousal disorder (Pryde et al 2006). It was suggested that, by selective NEP inhibition, VIP levels could increase thereby enhance VIP-induced increase in vaginal blood flow (Pryde et al 2006). NEP is widely distributed and is present in the endothelial surface of several tissues where other important related peptidases are also located, such as angiotensin I-converting enzyme (ACE).…”

Section: Neprilysin Carboxydipeptidase Specificity Studies and Improvmentioning

confidence: 99%

The use of Fluorescence Resonance Energy Transfer (FRET) peptidesfor measurement of clinically important proteolytic enzymes

Carmona

Juliano

2009

An. Acad. Bras. Ciênc.

View full text Add to dashboard Cite

Proteolytic enzymes have a fundamental role in many biological processes and are associated with multiple pathological conditions. Therefore, targeting these enzymes may be important for a better understanding of their function and development of therapeutic inhibitors. Fluorescence Resonance Energy Transfer (FRET) peptides are convenient tools for the study of peptidases specificity as they allow monitoring of the reaction on a continuous basis, providing a rapid method for the determination of enzymatic activity. Hydrolysis of a peptide bond between the donor/acceptor pair generates fluorescence that permits the measurement of the activity of nanomolar concentrations of the enzyme. The assays can be performed directly in a cuvette of the fluorimeter or adapted for determinations in a 96-well fluorescence plate reader. The synthesis of FRET peptides containing ortho-aminobenzoic acid (Abz) as fluorescent group and 2,4-dinitrophenyl (Dnp) or N-(2,4-dinitrophenyl)ethylenediamine (EDDnp) as quencher was optimized by our group and became an important line of research at the Department of Biophysics of the Federal University of São Paulo. Recently, Abz/Dnp FRET peptide libraries were developed allowing high-throughput screening of peptidases substrate specificity. This review presents the consolidation of our research activities undertaken between 1993 and 2008 on the synthesis of peptides and study of peptidases specificities.

show abstract

Novel Selective Inhibitors of Neutral Endopeptidase for the Treatment of Female Sexual Arousal Disorder. Synthesis and Activity of Functionalized Glutaramides

Cited by 36 publications

References 35 publications

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

Recent Advances in Discovery and Development of Medicines for the Treatment of Secretory Diarrhea in the Developing World

The use of Fluorescence Resonance Energy Transfer (FRET) peptidesfor measurement of clinically important proteolytic enzymes

Contact Info

Product

Resources

About