A key structural element differentiating the second generation HIV-1 maturation inhibitor (MI) GSK3532795 from earlier MIs is a C-linked phenyl ring incorporated at the C-3 position of the triterpenoid core of betulinic acid. The phenyl ring that replaces the dimethylated succinate ester characteristic of bevirimat and related compounds preserves the pharmacophore while providing other advantages including lower affinity for binding to human serum. GSK3532795 demonstrated proof-of-concept in a Phase IIa clinical study in HIV-1 infected patients, but its development was discontinued due to gastrointestinal intolerability and the emergence of resistant viruses. Additional structural refinement and careful mapping of the C-3 pharmacophoric element was performed in order to identify effective isosteres of the phenyl group which further improved the antiviral profile and PK properties of GSK3532795 and which were not associated with gastrointestinal problems over long term dosing. As a result of these studies, several effective replacements for the phenyl ring of GSK3532795 were identified including a series of cyclohexenes and a novel spiro[3,3]hept-5-ene moiety that provide new vectors for substitution. These investigations ultimately led to the discovery of the next generation MI inhibitor GSK3640254 which is currently being evaluated in Phase IIb clinical trials.

Exploration of phenyl isosteres in the context of HIV-1 maturation inhibitors

ACS Fall 2021

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