Document Detail

Comparison of nodulisporic acid analogs in a Lucilia sericata in vitro assay and a Ctenocephalides felis membrane feeding system.
MedLine Citation:
PMID:  12053989     Owner:  NLM     Status:  MEDLINE    
A medicinal chemistry program on the nodulisporic acid chemical class, guided by an artificial membrane flea-feeding assay, has recently identified permissive and nonpermissive regions of the pharmacophore for exploitation against fleas. This pathway was validated when several promising compounds from this program were administered orally to dogs at 15.0 mg/kg and found to have >90% flea activity for 2 wk. To determine if a surrogate insect assay would have provided the same guidance, a nodulisporic acid analog series was examined in both a Lucilia sericata larval assay and an artificial membrane flea-feeding assay using Ctenocephalides felis. Results from both insect assays were concordant in that even subtle chemical modification or substitution to the left-hand side of the nodulisporic acid pharmacophore resulted in substantial loss of insecticidal activity. Both assays were also in general agreement that the only modifications to the pharmacophore that did not result in loss of activity occurred to the C-8 side chain on the right-hand side of the molecule. Although there was good agreement between the 2 assays on the general regions of the pharmacophore, there was variance on individual compounds in the mono- and disubstituted amide series from the C-8 side chain. For example, the L. sericata assay showed several analogs from this subclass to possess similar activity to the parent acid, whereas the membrane assay indicated superior activity against fleas relative to the same parent. Consequently, although there was substantial general agreement between the assays, it was concluded that finer optimization of a lead compound should be done against the target parasite, even if it is ex vivo, as early as possible in a medicinal chemistry program.
T Felcetto; J Ondeyka; S L Colletti; P T Meinke; W L Shoop
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  The Journal of parasitology     Volume:  88     ISSN:  0022-3395     ISO Abbreviation:  J. Parasitol.     Publication Date:  2002 Apr 
Date Detail:
Created Date:  2002-06-10     Completed Date:  2002-06-27     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7803124     Medline TA:  J Parasitol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  223-6     Citation Subset:  IM    
Merck Research Laboratories, Merck and Co., Inc., Rahway, New Jersey 07065, USA.
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MeSH Terms
Diptera / metabolism*
Fleas / metabolism*
Membranes, Artificial
Structure-Activity Relationship
Reg. No./Substance:
0/Indoles; 0/Insecticides; 0/Membranes, Artificial; 0/nodulisporic acid A

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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