Microbial models of mammalian metabolism. Biotransformations of HP 749 (besipirdine) using Cunninghamella elegans.

HP 749 (besipirdine; Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ) and related analogs belonging to the N-(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 nonadrenergic activities both in vitro and in 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 of N-dealkylation (2%), and sequential N-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.