The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation

Abstract

GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The key structural difference between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3 position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic acid substituted with a CH2F moiety at the carbon atom α- to the pharmacophoric carboxylic acid. This structural element provided a new vector with which to explore structure–activity relationships (SARs) and led to compounds with improved polymorphic coverage while preserving pharmacokinetic (PK) properties. The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7–10 days of dosing to HIV-1-infected subjects.

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

“…A Suzuki coupling reaction between vinyl triflate 31 and pinacol boronate (S)-32 in the presence of XPhos-Pd-G2 afforded 33 in 49% yield. 50 Compounds 6 and 7 were prepared in two additional steps from intermediate 33. Alkylation of the C-17 amine of 33 with either commercially available 4-(2chloroethyl)morpholine hydrochloride or 1-(2-chloroethyl)-4-(methylsulfonyl)piperazine in the presence of K 3 PO 4 and KI provided the respective monoalkylated products.…”

“…The synthesis of compounds 4 and 5 was previously described. 50 The synthetic routes to the C-17 fragments are illustrated in Schemes 2−5. Preparation of 40 was completed in six steps from commercially available tetrahydro-4H-thiopyran-4-one (35) (Scheme 2).…”

“…1-(4-Allyl-4-hydroxypiperidin-1-yl)ethanone (51). To a solution of 1-acetylpiperidin-4-one (50) (1.00 g, 7.08 mmol) in THF (50 mL) at −10 °C (acetone/ice bath) was added allylmagnesium bromide (7.44 mL, 7.44 mmol, 1 M in Et 2 O). The reaction mixture was stirred at −10 °C for 30 min.…”

“…There was no significant difference in potency when the stereocenter at the α-position of the carboxylic acid was inverted as illustrated by a comparison of 5 to 4. 50 The virology profiles of three related analogues that contain either a morpholine (6, pK a = 8.2), 4-(methylsulfonyl)piperazine (7), or 4-methylpiperidin-4-ol moiety (8) are shown in Table 1. These compounds had a higher shift in potency in the presence of human serum compared to 4 and 5 and in the case of 6 had modestly reduced potency against the T332S/V362I/ prR41G-containing virus.…”

“…In this PK study, an increase in exposure was observed (AUC tot = 35.5 μM•h), resulting in an increased oral bioavailability of 31%. 50 The synthetic routes to the C-17 fragments are illustrated in Schemes 2−5. Preparation of 40 was completed in six steps from commercially available tetrahydro-4H-thiopyran-4-one (35) (Scheme 2).…”