Posaconazole (Noxafil, SCH 56592), a new azole antifungal drug, was a discovery based on the isolation and mass spectral characterization of a circulating metabolite of an earlier lead (SCH 51048).
Posaconazole (SCH 56592) is a novel triazole antifungal drug that is marketed in Europe and the United States under the trade name 'Noxafil' for prophylaxis against invasive fungal infections. SCH 56592 was discovered as a possible active metabolite of SCH 51048, an earlier lead. Initial studies have shown that serum concentrations determined by a microbiological assay were higher than those determined by HPLC from animals dosed with SCH 51048. Subsequently, several animals species were dosed with (3)H-SCH 51048 and the serum was analyzed for total radioactivity, SCH 51048 concentration and antifungal activity. The antifungal activity was higher than that expected based on SCH 51048 serum concentrations, confirming the presence of active metabolite(s). Metabolite profiling of serum samples at selected time intervals pinpointed the peak that was suspected to be the active metabolite. Consequently, (3)H-SCH 51048 was administered to a large group of mice, the serum was harvested and the metabolite was isolated by extraction and semipreparative HPLC. LC-MS/MS analysis suggested that the active metabolite is a secondary alcohol with the hydroxyl group in the aliphatic side chain of SCH 51048. All corresponding monohydroxylated diastereomeric mixtures were synthesized and characterized. The HPLC retention time and LC-MS/MS spectra of the diastereomeric secondary alcohols of SCH 51048 were similar to those of the isolated active metabolite. Finally, all corresponding individual monohydroxylated diasteriomers were synthesized and evaluated for in vitro and in vivo antifungal potencies, as well as pharmacokinetics. SCH 56592 emerged as the candidate with the best overall profile.
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. amin.nomeir@spcorp.com
Amin A
AA
Nomeir
Birendra N
BN
Pramanik
Larry
L
Heimark
Frank
F
Bennett
John
J
Veals
Peter
P
Bartner
Maryjane
M
Hilbert
Anil
A
Saksena
Paul
P
McNamara
Viyyoor
V
Girijavallabhan
Ashit K
AK
Ganguly
Raymond
R
Lovey
Russell
R
Pike
Haiyan
H
Wang
Yi-Tsung
YT
Liu
Pramila
P
Kumari
Walter
W
Korfmacher
Chin-Chung
CC
Lin
Anthony
A
Cacciapuoti
David
D
Loebenberg
Roberta
R
Hare
George
G
Miller
Cecil
C
Pickett
D000818:Animals; D000935:Antifungal Agents / Q000032:analysis* / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D015195:Drug Design; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008815:Mice, Inbred Strains; D011817:Rabbits; D014230:Triazoles / Q000032:analysis* / Q000097:blood / Q000493:pharmacokinetics*
D000935:Antifungal Agents; C094161:SCH 51048; D014230:Triazoles; C101425:posaconazole