3,3′-{[(Biphenyl-2,2′-diyl)bis(methylene)]bis(oxy)}bis[N-(4-chlorophenyl)benzamide]

In the title compound, C40H30Cl2N2O4, the two benzene rings of the biphenyl unit are twisted with respect to each other, making a dihedral angle of 73.07 (4)°. The benzene rings of the benzamide groups form dihedral angles of 77.09 (5) and 55.48 (6)° with the central biphenyl moiety. In the crystal, molecules are linked through N—H...O hydrogen bonds to form a fused R22(38) ring motif which forms a supermolecular ribbon network extending along the [100] plane. In the two 4-chlorophenyl rings, the five C atoms and their attached H atoms are disordered over two sets of sites, with site-occupancy factors of 0.657 (15):0.343 (15) and 0.509 (13):0.491 (13)

Coupling of an Acyl Migration Prodrug Strategy with Bio-activation To Improve Oral Delivery of the HIV‑1 Protease Inhibitor Atazanavir

HIV-1 protease inhibitors (PIs), which include atazanavir (ATV, <b>1</b>), remain important medicines to treat HIV-1 infection. However, they are characterized by poor oral bioavailability and a need for boosting with a pharmacokinetic enhancer, which results in additional drug–drug interactions that are sometimes difficult to manage. We investigated a chemo-activated, acyl migration-based prodrug design approach to improve the pharmacokinetic profile of <b>1</b> but failed to obtain improved oral bioavailability over dosing the parent drug in rats. This strategy was refined by conjugating the amine with a promoiety designed to undergo bio-activation, as a means of modulating the subsequent chemo-activation. This culminated in a lead prodrug that (1) yielded substantially better oral drug delivery of <b>1</b> when compared to the parent itself, the simple acyl migration-based prodrug, and the corresponding simple l-Val prodrug, (2) acted as a depot which resulted in a sustained release of the parent drug in vivo, and (3) offered the benefit of mitigating the pH-dependent absorption associated with <b>1</b>, thereby potentially reducing the risk of decreased bioavailability with concurrent use of stomach-acid-reducing drugs

Coupling of an Acyl Migration Prodrug Strategy with Bio-activation To Improve Oral Delivery of the HIV‑1 Protease Inhibitor Atazanavir

HIV-1 protease inhibitors (PIs), which include atazanavir (ATV, <b>1</b>), remain important medicines to treat HIV-1 infection. However, they are characterized by poor oral bioavailability and a need for boosting with a pharmacokinetic enhancer, which results in additional drug–drug interactions that are sometimes difficult to manage. We investigated a chemo-activated, acyl migration-based prodrug design approach to improve the pharmacokinetic profile of <b>1</b> but failed to obtain improved oral bioavailability over dosing the parent drug in rats. This strategy was refined by conjugating the amine with a promoiety designed to undergo bio-activation, as a means of modulating the subsequent chemo-activation. This culminated in a lead prodrug that (1) yielded substantially better oral drug delivery of <b>1</b> when compared to the parent itself, the simple acyl migration-based prodrug, and the corresponding simple l-Val prodrug, (2) acted as a depot which resulted in a sustained release of the parent drug in vivo, and (3) offered the benefit of mitigating the pH-dependent absorption associated with <b>1</b>, thereby potentially reducing the risk of decreased bioavailability with concurrent use of stomach-acid-reducing drugs