Ismail Ghazzouli
Bristol-Myers Squibb
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Featured researches published by Ismail Ghazzouli.
Annals of the New York Academy of Sciences | 1990
Joanne J. Bronson; Hsu-Tso Ho; Hilde De Boeck; Ismail Ghazzouli; John C. Martin; Michael J. M. Hitchcock
Our studies have shown that the acyclic nucleotide analogues PMEA and HPMPC are able to penetrate into cells and are then activated to mono- and diphosphate derivatives. The latter correspond to triphosphate analogues and presumably serve an important role in the biological activity exerted by these antiviral agents. In support of this idea, the inhibitory effect of PMEApp on HIV reverse transcriptase has been demonstrated with both RNA and DNA template-primer systems. Further studies will be undertaken to determine the effect of HPMPCpp on viral DNA polymerases. Whereas the metabolism of PMEA in CEM cells gives rise to only PMEAp and PMEApp, additional metabolites were obtained in MRC-5 cells; the identity of these metabolites remains to be determined. In the case of HPMPC, a third metabolite was obtained in addition to HPMPCp and HPMPCpp, which has been tentatively assigned as a phosphate-choline adduct by analogy with activation of cytosine-based nucleoside derivatives. The metabolism of HPMPC was unchanged between uninfected and infected cells, indicating that viral enzymes are not necessary for the activation of HPMPC. The long intracellular half-lives of the HPMPC metabolites may have implications for the antiviral efficacy of this compound. The persistence of activated metabolites suggests that infrequent dosing may be possible due to a prolonged antiviral effect. Our results on the effectiveness of infrequent dosing schedules with HPMPC in the treatment of HSV 2 infections in mice support this hypothesis. It is also possible that HPMPCp-choline may serve as a reservoir for HPMPC and therefore for the presumed active metabolite HPMPCpp.
Advances in Experimental Medicine and Biology | 1990
Joanne J. Bronson; Louis M. Ferrara; Michael J. M. Hitchcock; Hsu-Tso Ho; Ismail Ghazzouli; Earl R. Kern; Kenneth F. Soike; John C. Martin
(S)-1-(3-Hydroxy-2-(phosphonylmethoxy)propyl)cytosine (HPMPC; 1, fig. 1, left) has been identified from a series of phosphonate nucleotide analogues as having the greatest therapeutic index against lethal herpes simplex virus (HSV) infections in mice (1, 2). The prototype compound of the series is the adenine analogue 2 (HPMPA; 2, fig. 1, right), which was first described by De Clercq et al. in 1986 as a broad-spectrum antiviral agent (3). HPMPA was shown to have a mechanism of action that involves, at least in part, two intracellular phosphorylations to give a diphosphate, which then selectively inhibits the viral polymerase. Since the discovery of HPMPA, additional studies have shown that many related phosphonylmethoxy nucleotide analogues have broad-spectrum in vitro activity (4, 5). Of this class of nucleotide analogues, HPMPC has been described as having the best in vitro therapeutic index against cytomegalovirus (CMV) (2, 6).
Nucleosides, Nucleotides & Nucleic Acids | 1989
John C. Martin; Muzammia M. Mansuri; John E. Starrett; Jean-Pierre Sommadossi; Vera Brankovan; Ismail Ghazzouli; H-T. Ho; Michael J. M. Hitchcock
Abstract D4T is a thymidine analogue with an in vitro potency against HIV comparable to that of AZT but is less toxic to a variety of cell lines including human hemopoietic progenitor cells.
Nucleosides, Nucleotides & Nucleic Acids | 1989
Roman Z. Sterzycki; Muzammil M. Mansuri; V. Brankovan; R. Buroker; Ismail Ghazzouli; Michael J. M. Hitchcock; J-P. Somrnadossi; John C. Martin
Abstract 3′-Deoxy-3′-fluorothymidine was prepared and evaluated as a potential anti-AIDS agent.
Nucleosides, Nucleotides & Nucleic Acids | 1989
Choung U. Kim; Bing Y. Luh; Peter F. Misco; Joanne J. Bronson; Michael J. M. Hitchcock; Ismail Ghazzouli; John C. Martin
Abstract Syntheses and biological activities of 2-phosphonylmethoxy-ethyl (PME) purine analogs are described.
Nucleosides, Nucleotides & Nucleic Acids | 1989
John C. Martin; Joanne J. Bronson; Robert R. Webb; Michael M. J. Hitchcock; Ismail Ghazzouli
Abstract Of a series of phosphonate nucleotide analogues, HPMPC (2) showed the greatest in vivo therapeutic index against herpes simplex viruses.
Journal of Medicinal Chemistry | 1989
Mansuri Mm; Starrett Je; Ismail Ghazzouli; Michael J. M. Hitchcock; Sterzycki Rz; Brankovan; Lin Ts; August Em; Prusoff Wh; Sommadossi Jp
Journal of Medicinal Chemistry | 1987
Tai Shun Lin; Ming S. Chen; Colin McLaren; You Song Gao; Ismail Ghazzouli; William H. Prusoff
Journal of Medicinal Chemistry | 1989
Joanne J. Bronson; Ismail Ghazzouli; Michael J. M. Hitchcock; Robert R. Webb; John C. Martin
Journal of Medicinal Chemistry | 1990
Choung U. Kim; Bing Y. Luh; Peter F. Misco; Joanne J. Bronson; Michael J. M. Hitchcock; Ismail Ghazzouli; John C. Martin