Candoxatril

Candoxatril is the orally active prodrug[1] of candoxatrilat (UK-73967).

Candoxatril
Names
Preferred IUPAC name
(1R,4s)-4-(1-{(2S)-3-[(2,3-Dihydro-1H-inden-5-yl)oxy]-2-[(2-methoxyethoxy)methyl]-3-oxopropyl}cyclopentan-1-amido)cyclohexane-1-carboxylic acid
Identifiers
CAS Number
3D model (JSmol)
ChEMBL
ChemSpider
DrugBank
MeSH candoxatril
PubChem CID
UNII
InChI
  • InChI=1S/C29H41NO7/c1-35-15-16-36-19-23(27(33)37-25-12-9-20-5-4-6-22(20)17-25)18-29(13-2-3-14-29)28(34)30-24-10-7-21(8-11-24)26(31)32/h9,12,17,21,23-24H,2-8,10-11,13-16,18-19H2,1H3,(H,30,34)(H,31,32)
SMILES
  • O=C(NC1CCC(C(=O)O)CC1)C4(CC(C(=O)Oc2cc3c(cc2)CCC3)COCCOC)CCCC4
Properties
Chemical formula
 C29H41NO7
Molar mass 515.647 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Human neutral endopeptidase

Human neutral endopeptidase (neprilysin) as the neutral endopeptidase 24.11[2] complexed (RB-101) with phosphoramidon degrades and inactivates[3] a number of bioactive peptides. Two multiply connected folding domains[3] of the neutral endopeptidase locus[3] splicing of exons 1, 2a, or 2b to the common exon 3 composed of 24 exons of the human CALLA/NEP gene[2] containing the active site, it is known as peptidase family M13 (neprilysin family, clan MA(E)) the gluzincins a faint but significant structural relationship of the metzincins[4][5][6][7] to the thermolysin-like enzymes,[5] Zincin is the simplest descriptor of biological space.[8] The structure reveals two multiply connected folding domains which embrace a large central cavity containing the active site of the 5-indanyl ester prodrug candoxatril[9] and differs from phosphoramidon [N-(N-(((6-Deoxy-α-L-mannopyranosyl)oxy)hydroxyphosphinyl)-L- leucyl)-L-tryptophan] in several respects the structure of human neutral endopeptidase complexed with phosphoramidon is lost due to desolvation[9] of the enzyme and ligand on formation of the complex candoxatril.

Studies

Candoxatril is the first drug of its kind to be released for clinical trials regarding heart failure. This is because candoxatril produces favorable haemodynamic effects in patients with chronic heart failure. It has been demonstrated that candoxatril is associated with a beneficial hemodynamic effect that is useful both in rest and exercise. In several different studies, candoxatril has been shown to improve performance in people with heart failure. In one study, 12 different patients were selected, all with moderately severe heart failure. On day one of this study, the candoxatril had increased plasma ANP levels, suppressed aldosterone and decreased right atrial and pulmonary capillary wedge pressures. After treatment for 10 days, patients health had improved with an increase of basal ANP and a decrease of aldosterone, along with a reduced body weight that could be a reflection of chronic natriuretic, diuretic effects, or both. It was decided that on day 10 of the study, the effects of candoxatril were similar to that on day one.[10]

In a separate study, patients were gathered throughout the United Kingdom from 16 different centers. Over a four-week bind, the patients were either given candoxatril or placebo for the 84 days and every 28 days, patients were reassessed. Out of the 110 patients, 56 received candoxatril and 54 received the placebo. Over the time of the study, the patients who were taking candoxatril had an overall improvement in exercise time compared to the patients taking the placebo.[11]

In a third study, there was only one patient who experienced worsening heart failure during this particular study. However, the frequency was not statistically significantly different from another observed group that was on placebo. Together, the results of this study show the candoxatril offers a new, effective therapeutic in the treatment of people with mild heart failure. The beneficial effects may begin to improve the well-being of patients during everyday activities.[12]

See also

References
  1. Maw GN, Stobie A, Planken S, Pryde DC, Sanderson V, Platts MY, Corless M, Stacey P, Wayman C, Van Der Graaf P, Kohl C, Coggon S, Beaumont K (January 2006). "The discovery of small molecule inhibitors of neutral endopeptidase. Structure-activity studies on functionalized glutaramides". Chemical Biology Drug Design. 67 (1): 74–77. doi:10.1111/j.1747-0285.2005.00320.x. PMID 16492151.
  2. D'Adamio L, Shipp MA, Masteller EL, Reinherz EL (September 1989). "Organization of the gene encoding common acute lymphoblastic leukemia antigen (neutral endopeptidase 24.11): multiple miniexons and separate 5' untranslated regions". Proc Natl Acad Sci U S A. 86 (18): 7103–7107. Bibcode:1989PNAS...86.7103D. doi:10.1073/pnas.86.18.7103. PMC 298003. PMID 2528730.
  3. Oefner C; D'Arcy A; Hennig M; Winkler FK; Dale GE (February 2000). "Structure of human neutral endopeptidase (Neprilysin) complexed with phosphoramidon". J. Mol. Biol. 296 (2): 341–349. doi:10.1006/jmbi.1999.3492. PMID 10669592.
  4. Nigel M. Hooper (October 1994). "Families of zinc metalloproteases". FEBS Lett. 354 (1): 1–6. doi:10.1016/0014-5793(94)01079-X. PMID 7957888. S2CID 25374738.
  5. Stöcker W, Grams F, Baumann U, Reinemer P, Gomis-Rüth FX, McKay DB, Bode W (May 1995). "The metzincins--topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases". Protein Sci. 4 (5): 823–840. doi:10.1002/pro.5560040502. PMC 2143131. PMID 7663339.
  6. "Neutral zinc metallopeptidases, zinc-binding region signature as a superfamily, known as the metzincins (EC 3.4.15.1). ExPASy: PDOC00129".
  7. "EC 3.4.15.1 - Peptidyl-dipeptidase A in contrast to EC 3.4.15.4 atriopeptin. EMBL-EBI: PDOC00129".
  8. McArdle BM, Quinn RJ (April 2007). "Identification of Protein Fold Topology Shared between Different Folds Inhibited by Natural Products". ChemBioChem. 8 (7): 788–798. doi:10.1002/cbic.200700035. PMID 17429823. S2CID 21061622.
  9. Holland, D.R.; Barclay, P.L.; Danilewicz, J.C.; Matthews, B.W.; James, K. (January 1994). "Inhibition of thermolysin and neutral endopeptidase 24.11 by a novel glutaramide derivative: X-ray structure determination of the thermolysin-inhibitor complex". Biochemistry. 33 (1): 51–56. doi:10.1021/bi00167a007. PMID 8286362.
  10. "Result Filters." National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 23 Nov. 2015.
  11. McDowell, G., W. Coutie, C. Shaw, K. D. Buchanan, A. D. Struthers, and D. P. Nicholls. "The Effect of the Neutral Endopeptidase Inhibitor Drug, Candoxatril, on Circulating Levels of Two of the Most Potent Vasoactive Peptides." British Journal of Clinical Pharmacology. U.S. National Library of Medicine, n.d. Web. 23 Nov. 2015.
  12. McMurray, John. "Clinical Cardiology: New Frontiers." American Heart Association. American Heart Association, n.d. Web.
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