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)

Q4 · CHEMISTRY

Article

Author: Birendra N. Pramanik ; Maryjane Hilbert ; Walter Korfmacher ; John Veals ; Haiyan Wang ; George Miller ; Roberta Hare ; Russell Pike ; Ashit K. Ganguly ; Paul McNamara ; Chin-Chung Lin ; Anil Saksena ; Raymond Lovey ; Frank Bennett ; Larry Heimark ; Viyyoor Girijavallabhan ; Pramila Kumari ; Cecil Pickett ; Yi-Tsung Liu ; Amin A. Nomeir ; Anthony Cacciapuoti ; David Loebenberg ; Peter Bartner

AbstractPosaconazole (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 3H‐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, 3H‐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. Copyright © 2007 John Wiley & Sons, Ltd.

01 Jan 2006·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Hydroxylated analogues of the orally active broad spectrum antifungal, Sch 51048 (1), and the discovery of posaconazole [Sch 56592; 2 or (S,S)-5]

Q4 · MEDICINE

Article

Author: Naginbhai M. Patel ; Yi-Tsung Liu ; Frank Bennett ; David Loebenberg ; Patrick Pinto ; Haiyan Wang ; Edwin Jao ; Amin Nomeir ; Eugene Moss ; Roberta S. Hare ; Russel Pike ; Ashit K. Ganguly ; Fred Menzel ; Raymond G. Lovey ; Anthony Cacciapuoti ; Anil K. Saksena ; Viyyoor M. Girijavallabhan

As part of a detailed study, the syntheses, biological activities, and pharmacokinetic properties of hydroxylated analogues of the previously described broad spectrum antifungal agents, Sch 51048 (1), Sch 50001 (3), and Sch 50002 (4), are described. Based on an overall superior profile, one of the alcohols, Sch 56592 (2), was selected for clinical studies.

01 Jul 2002·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Synthesis and antifungal activity of the 2,2,5-tetrahydrofuran regioisomers of SCH 51048

Q4 · MEDICINE

Article

Author: Paul Blundell ; Anil K Saksena ; Raymond G Lovey ; Viyyoor M Girijavallabhan ; Henry Guzik ; Raulo M Parmegiani ; David Loebenberg ; Anthony Cacciapuoti

The four 2,2,5-regioisomer counterparts of SCH 51048 were synthesized and evaluated. As with the parent series, only the two cis isomers possessed any in vitro activity, and only the activity of the isomer with the R-configuration at the tetrahydrofuran 2-carbon was significant. The activity data suggests that oxygen at only one of the two possible ring positions benzylic to the difluorobenzene participates usefully in active site binding.

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Indication	Highest Phase	Country/Location	Organization	Date
Aspergillosis	Discovery	US	Schering-Plough Corp.	-
Cryptococcosis	Discovery	US	Schering-Plough Corp.	-

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