Synthetic Approaches to a Key Pyridone-carboxylic Acid Precursor Common to the HIV-1 Integrase Strand Transfer Inhibitors Dolutegravir, Bictegravir, and Cabotegravir

Abstract

Dolutegravir (DTG), Bictegravir (BIC), and Cabotegravir (CAB) are the second-generation integrase strand transfer inhibitors (INSTIs) that have been FDA-approved for the treatment of HIV-1 infection. Preparation of these INSTIs utilizes the common intermediate 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (6). Presented herein is a literature and patent review of synthetic routes used to access the pharmaceutically important intermediate 6.The review highlights the ways in which small fine-tuned synthetic modifications have been used to achieve good yields and regioselectivity of ester hydrolysis.

N-Substituted Bicyclic Carbamoyl Pyridones: Integrase Strand Transfer Inhibitors that Potently Inhibit Drug-Resistant HIV-1 Integrase Mutants

“…Carbamoyl pyridone-based compounds can chelate the Mg 2+ ions in the IN active site, blocking the ST reaction. The BiCAP pharmacophore serves as a critical component of all FDA-approved INSTIs. − We have developed a one-pot synthetic methodology that provides facile access to BiCAPs (see , and Supporting Information). We have a long-standing interest in developing bicyclic INSTIs, with a focus on compounds that retain antiviral efficacy against resistant mutant forms of IN. ,− We recently prepared a set of N -substituted BiCAPs of types 6 and 7 , that can be derived from a common pyridone-acetal intermediate 8 (Figure ).…”

“…The BiCAP pharmacophore serves as a critical component of all FDA-approved INSTIs. 35 − 38 We have developed a one-pot synthetic methodology that provides facile access to BiCAPs (see 39 , 40 and Supporting Information ). We have a long-standing interest in developing bicyclic INSTIs, with a focus on compounds that retain antiviral efficacy against resistant mutant forms of IN.…”

“… DTG, CAB, their simplified BiCAP congeners 6 and 7 , 35 , 36 , 40 and the key synthetic precursor 8 . 39 , 40 …”