Synthesis, Structure–Activity Relationships, and In Vivo Evaluation of Novel C-17 Amine Derivatives Based on GSK3640254 as HIV-1 Maturation Inhibitors with Broad Spectrum Activity

Abstract

An investigation of the structure−activity relationships of a series of HIV-1 maturation inhibitors (MIs) based on GSK3640254 (4) was conducted by incorporating novel C-17 amine substituents to reduce the overall basicity of the resultant analogues. We found that replacement of the distal amine on the C-17 sidechain present in 4 with a tertiary alcohol in combination with either a heterocyclic ring system or a cyclohexyl ring substituted with polar groups provided potent wild-type HIV-1 MIs that also retained excellent potency against a T332S/V362I/prR41G variant, a laboratory strain that served as a surrogate to assess HIV-1 polymorphic virus coverage. Compound 26 exhibited broad-spectrum HIV-1 activity against an expanded panel of clinically relevant Gag polymorphic viruses and had the most desirable overall profile in this series of compounds. In pharmacokinetic studies, 26 had low clearance and exhibited 24 and 31% oral bioavailability in rats and dogs, respectively.

Selected Plant Triterpenoids and Their Derivatives as Antiviral Agents

“…A comparison of basic anti-HIV-1 activity values is shown in Table 4. An overall summary of antiviral activity values of compounds 17-17s, 18, and 19 is presented in Table 5 [46][47][48]. Structurally similar compounds to those mentioned above [46][47][48] were reported recently as second-generation maturation inhibitors (compounds 20-22 and 23a-23e; Figure 4), displaying effect higher than bevirimat (3) against HIV-1 subtype C [49].…”

“…A replacement of the amine group on the C-17 side chain present in 17s with a tertiary alcohol in combination with either a heterocyclic ring system or a cyclohexyl ring substituted with polar groups provided potent wild-type (WT) HIV-1 maturation inhibitors. They also preserved excellent potency against a T332S/V362I/prR41G variant, a laboratory strain that served as a substitute to assess HIV-1 polymorphic virus characteristics [47]. Compound 19 exhibited a broad anti-HIV-1 activity against relevant Gag polymorphic viruses, and displayed the most desirable overall profile in this series of the studied compounds.…”

“…Compounds 18 and 19 had the most desirable overall profile in this series and were evaluated in rat and dog pharmacokinetic studies [47,48]. A comparison of basic anti-HIV-1 activity values is shown in Table 4.…”

“…A comparison of basic anti-HIV-1 activity values is shown in Table 4. An overall summary of antiviral activity values of compounds 17-17s, 18, and 19 is presented in Table 5 [46][47][48]. The investigation of the structure-activity relationships of a series of HIV-1 maturation inhibitors based on the compound 17s (Figure 3) continued by the subsequent incorporation of novel C-17 amine substituents to reduce the overall basicity of the target compounds [47].…”

“…An overall summary of antiviral activity values of compounds 17-17s, 18, and 19 is presented in Table 5 [46][47][48]. The investigation of the structure-activity relationships of a series of HIV-1 maturation inhibitors based on the compound 17s (Figure 3) continued by the subsequent incorporation of novel C-17 amine substituents to reduce the overall basicity of the target compounds [47]. A replacement of the amine group on the C-17 side chain present in 17s with a tertiary alcohol in combination with either a heterocyclic ring system or a cyclohexyl ring substituted with polar groups provided potent wild-type (WT) HIV-1 maturation inhibitors.…”