Microbial synthesis of three metabolites of a tachykinin receptor antagonist, TAK-637.
The compound TAK-637 ((aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione), a tachykinin receptor antagonist, has been shown to be converted into three metabolites in rats and guinea pigs. It was difficult to isolate the metabolites from rats and guinea pigs administered TAK-637 and elucidate the structures. A total of 100 actinomycete strains were screened for the ability to convert TAK-637 into its metabolites. Three strains, Streptomyces subrutilus IFO13388, Streptomyces tanashiensis subsp. cephalomyceticus IFO13929 and Streptomyces lavenduligriseus IFO13405, were found to convert TAK-637 into the metabolites consistent with the metabolites formed in rats and guinea pigs as determined by HPLC analyses. The metabolites were synthesized by microbial conversion using the actinomycetes. The structures of the metabolites were elucidated by spectral analyses. It was found that the methyl group at the C(5)-phenyl group of TAK-637 was hydroxylated and the resulting alcohol was converted to carboxylic acid via aldehyde. One of the metabolites (hydroxylated TAK-637) was obtained using a 200-l fermentor in a large-scale cultivation to evaluate its biological activity.
Tarui
N
N
Pharmaceutical Research Division, Takeda Chemical Industries Ltd., 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Tarui_Naoki@takeda.co.jp
Ikeura
Y
Y
Natsugari
H
H
Nakahama
K
K