Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Attachment 6. Preclinical and Human Pharmacokinetic Profiling of BMS-663749, a Phosphonooxymethyl Prodrug of the HIV-1 Attachment Inhibitor 2-(4-Benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043)

Abstract

BMS-663749, a phosphonooxymethyl prodrug 4 of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043) (2) was prepared and profiled in a variety of preclinical in vitro and in vivo models designed to assess its ability to deliver parent drug following oral administration. The data showed that prodrug 4 had excellent potential to significantly reduce dissolution rate-limited absorption following oral dosing in humans. Clinical studies in normal healthy subjects confirmed the potential of 4, revealing that the prodrug significantly increased both the AUC and C(max) of 2 compared to a solid capsule formulation containing the parent drug upon dose escalation. These data provided guidance for further efforts to obtain an effective HIV-1 attachment inhibitor.

In VitroAntiviral Characteristics of HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068

“…The prodrug is thought to be cleaved by alkaline phosphatase, located on the luminal surface of the small intestine brush border membranes, releasing BMS-626529. Due to its good membrane permeability, BMS-626529 is then rapidly absorbed (20,37). In healthy volunteers, BMS-663068 demonstrated good exposure following oral administration, reflecting effective conversion to BMS-626529 and subsequent rapid absorption (20).…”

“…Due to its good membrane permeability, BMS-626529 is then rapidly absorbed (20,37). In healthy volunteers, BMS-663068 demonstrated good exposure following oral administration, reflecting effective conversion to BMS-626529 and subsequent rapid absorption (20). The pharmacokinetic pro-file of BMS-663068 was further optimized by the development of an extended-release formulation (31).…”

Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41

“…Despite the improvements discussed above, this compound also suffered from low solubility and poor intrinsic dissolution properties, which were addressed by making the phosphonooxymethyl prodrug BMS-663068, another small-molecule attachment inhibitor targeting HIV-1 gp120 [59]. Its development was based on improved results from an earlier prodrug, BMS-663749, generated from the parent inhibitor BMS-488043 [61]. BMS-663068 was expected to be cleaved by alkaline phosphatase in the small intestine to release BMS-626529, the active component of the prodrug BMS-663068, which showed good membrane permeability [61].…”

“…Its development was based on improved results from an earlier prodrug, BMS-663749, generated from the parent inhibitor BMS-488043 [61]. BMS-663068 was expected to be cleaved by alkaline phosphatase in the small intestine to release BMS-626529, the active component of the prodrug BMS-663068, which showed good membrane permeability [61]. This prodrug was tested on fifty HIV-1-infected subjects for 8 days in an open label, multiple dose parallel study.…”

Pyrroloaryls and pyrroloheteroaryls: Inhibitors of the HIV fusion/attachment, reverse transcriptase and integrase

“…Initially among the three synthesized compounds, two indole derivatives as 10a and 10b showed moderate to good potency, in which later one with fluorine atom was more strongly active with very low cytotoxicity at >300 µM of CC 50 level while much better EC 50 was prepared in order to overcome some drawbacks of BMS-488043 like solubility limited absorption, and examined among in vitro and in vivo preclinical models to assess its ability to deliver parent drug following oral administration. This prodrug was found to express enhanced pharmacokinetic properties, successfully overcoming the dissolution-and solubility-limited absorption [46]. Like BMS-488043, derivative 12b, a methyl phosphate prodrug of 12a, target gp120 receptor to exhibit its HIV-1 attachment inhibitory action.…”