GRL-04810 and GRL-05010, Difluoride-Containing Nonpeptidic HIV-1 Protease Inhibitors (PIs) That Inhibit the Replication of Multi-PI-Resistant HIV-1 In Vitro and Possess Favorable Lipophilicity That May Allow Blood-Brain Barrier Penetration

Substituted Bis-THF Protease Inhibitors with Improved Potency against Highly Resistant Mature HIV-1 Protease PR20

“…22 GRL-5010A also exhibits moderate antiviral activity against a highly darunavir resistant strain of HIV-1 selected in the laboratory. 22 Both GRL-4410A and GRL-5010A exhibit nanomolar inhibition of the proteolytic activity of PR20. The K i value of GRL-4410A for PR20 is 4.3 ± 7.0 nM, while that of GRL-5010A is 1.7 ± 1.8 nM.…”

“…Furthermore, the fluorine substituted GRL-5010A has 6.5-fold higher apparent permeability coefficient ( P app ), which is a measure of penetration efficiency of the drug across the blood–brain barrier, than darunavir. 22 Viral particles hidden in the central nervous system (CNS) are a major problem in the treatment of HIV, and improving the drug concentration in CNS may help reduce the incidence of HIV-1 associated dementia and other CNS disorders. 32,33 The current structures show that both of these inhibitors form direct, as well as water-mediated, interactions with the flap residue Gly 48 of PR20, similar to those of the wild-type PR.…”

“…21 The fluorine containing compound GRL-5010A was shown to have better blood–brain barrier penetration than darunavir. 22,23 Also, the two fluorines in GRL-5010A form interactions with the main chain atoms of flap residue Gly 48 in wild-type PR. 23 GRL-5010A is a potent inhibitor of wild-type PR with a K i of 5.8 pM and inhibits viral replication with an EC 50 of 0.003 μ M. 22 GRL-5010A also showed significantly better inhibition of the replication of seven tested multidrug resistant strains compared to saquinavir, lopinavir, atazanavir, amprenavir, and darunavir, with EC 50 values in the range of 0.002–0.02 μ M. 22 …”

A Modified P1 Moiety Enhances In Vitro Antiviral Activity against Various Multidrug-Resistant HIV-1 Variants and In Vitro Central Nervous System Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413

“…We also attempted to select for HIV-1 variants resistant to GRL-10413 by propagating the laboratory wild-type strain HIV-1 NL4-3 in MT-4 cells in the presence of increasing concentrations of GRL-10413, and we determined the amino acid substitutions that emerged in the protease region under the pressure of GRL-10413. Recently, we reported a few HIV PIs, GRL-04810, -05010, and -0739, that show good CNS penetration as tested in a blood-brain barrier (BBB) reconstruction model in vitro (20)(21)(22); structures and in vitro data for these three GRL-PIs are given in Table 1 and in Fig. S1 and Table S1 in the supplemental material.…”

A Novel Tricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor, GRL-0739, Effectively Inhibits the Replication of Multidrug-Resistant HIV-1 Variants and Has a Desirable Central Nervous System Penetration Property In Vitro

“…One such anti-HIV-1 agent, darunavir (DRV), which contains a structure-based designed privileged nonpeptidic P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF) (15)(16)(17), has been approved as a first-line therapeutic agent for the treatment of individuals who are infected with HIV-1. We also recently reported that a few HIV protease inhibitors, GRL-0519 containing tris-THF (18,19) and GRL-04810 and GRL-05010, show good CNS penetration in a blood-brain barrier (BBB) reconstruct model in vitro (20). In the present work, we examined and characterized the nonpeptidic HIV-1 protease inhibitor GRL-0739 (21), which contains the cyclohexyl-bis-THF moiety and a sulfonamide isostere (Fig.…”