Biotransformations of HP 749 (Besipirdine) UsingCunninghamella elegans
Abstract
HP 749 (besipirdine; Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ) and related analogs belonging to theN-(4-pyridinyl)-1H-indol-1-amine class of compounds have shown a potential to mitigate multiple biochemical deficits associated with Alzheimer’s disease. HP 749 has demonstrated cholinergic and noradrenergic activities both in vitro andin vivo, and has potential for the symptomatic treatment of Alzheimer’s disease. The three primary metabolites of HP 749 in dogs, rats, and humans result from hydroxylation of the indole ring,N-dealkylation of the parent compound, and sequential hydroxylation and dealkylation. The fungus Cunninghamella elegans (ATCC 36112) converts 25% of HP 749 in a dextrose broth to yield four metabolites, three of which have been reported in mammalian systems. Preparative scale fermentation allowed for the isolation of the major fungal metabolite resulting from hydroxylation of the indole nucleus at position 5 (16%), which was characterized by cochromatographic (TLC and HPLC), 1H-NMR, mass spectral (chemical ionization/MS), and UV comparisons to a synthetic standard. Additional minor fungal metabolites were formed as a result ofN-dealkylation (2%), and sequentialN-dealkylation and aromatic hydroxylation (2.5%). C. elegans is being used as a model to help predict and generate the logical mammalian metabolites of related structural analogs of HP 749.
Footnotes
-
Send reprint requests to: Geeta P. Rao, DuPont Merck, Stine-Haskell Research Center, Building 110/18, P.O. Box 30, Newark, DE 19714-0030.
- Abbreviations used are::
- DMF
- N,N-dimethyl formamide
- RF
- retardation factor
- ATCC
- American Type Culture Collection
- CI
- chemical ionization
- RT
- retention time
- COSY
- correlation spectroscopy
- Received November 8, 1996.
- Accepted February 26, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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