Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.24.11 (
CD10
)
9,792
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective
neutral endopeptidase
(
NEP
) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and
SAR
investigations are detailed. In particular, the strategy of starting with the clinically precedented selective
NEP
inhibitor, Candoxatrilat, and targeting low molecular weight and relatively polar mono-carboxylic acids is described. This led ultimately to the prototype development candidate R-13, for which detailed pharmacology and pharmacokinetic parameters are presented.(1)
...
PMID:Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder. Synthesis and activity of functionalized glutaramides. 1682
The dual inhibitory action of the pain related peptide opiorphin (H-Gln-Arg-Phe-Ser-Arg-OH) against
neutral endopeptidase
(
NEP
) and aminopeptidase N (AP-N) was further investigated by a
SAR
study involving minor modifications on the polar side chains of Arg residues and glycosylation with monosaccharides at Ser. None of them exerted dual or individual inhibitory potency superior than opiorphin. However, the correlations deduced offer further proof for the key role of these residues upon the binding and bioactive conformational stabilization of opiorphin. NMR conformational studies on the glycopeptides suggest that they are still very flexible compounds that may attain their respective bioactive conformations.
...
PMID:Influence of polar side chains modifications on the dual enkephalinase inhibitory activity and conformation of human opiorphin, a pain perception related peptide. 2646 33
Enkephalins are involved in a number of physiological processes. However, these peptides are quickly degraded by peptidases, e.g. the
neutral endopeptidase
(
NEP
). Inhibition of the enzymatic degradation of enkephalins is one of the possible approaches to prolong their activity. Selective inhibitor of
NEP
, sialorphin, is the attractive lead compound for enkephalins degradation studies. In this work, an alanine scan of sialorphin and a series of its hybrids with opiorphin, synthesised by the solid phase method, were performed. The effect of the peptides on degradation of Met-enkephalin by
NEP
in vitro was investigated. Molecular modelling technique was used to identify residues responsible for protein-ligand interactions. We showed that substitution of amino acids Gln
1
, Pro
4
and Arg
5
of sialorphin for Ala significantly reduced the half-life of Met-enkephalin in the presence of
NEP
. [Ala
3
]sialorphin displayed a higher inhibitory potency against
NEP
than sialorphin. Substitution of His
2
for Ala led to a compound which was as active as lead compound. Sialorphin has a structure which hardly tolerates substitution in its sequence at positions 1, 4 and 5. The conversion of His
2
for alanine in sialorphin is tolerated very well. The higher inhibitory potency of [Ala
3
]sialorphin than sialorphin against
NEP
is caused by removal of the hydrophilic residue (Asn) and a better fit of the peptide to the enzyme-binding pocket. The role of side chains of sialorphin in degradation of enkephalin by
NEP
has been explored. This study also provides an important
SAR
information essential for further drug design.
...
PMID:Alanine scan of sialorphin and its hybrids with opiorphin: synthesis, molecular modelling and effect on enkephalins degradation. 2975 65
