Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors

Abstract

Merck's MK-0518, known as raltegravir, has recently become the first FDA-approved HIV-1 integrase (IN) inhibitor and has since risen to blockbuster drug status. Much research has in turn been conducted over the last few years aimed at recreating but optimizing the compound's interactions with the protein. Resulting me-too drugs have shown favorable pharmacokinetic properties and appear drug-like but, as expected, most have a highly similar interaction with IN to that of raltegravir. We propose that, based upon conclusions drawn from our docking studies illustrated herein, most of these me-too MK-0518 analogues may experience a low success rate against raltegravir-resistant HIV strains. As HIV has a very high mutational competence, the development of drugs with new mechanisms of inhibitory action and/or new active substituents may be a more successful route to take in the development of second- and third-generation IN inhibitors.

Figure 1

The structure of diketo acid-based HIV-1 integrase inhibitors.

Figure 2

Requirements for "second generation drug" classification.

Figure 3

The evolution of dihydroxypyrimidine-4-carboxamides.

Figure 4

The evolution of N-methylpyrimidones.

Figure 5

Dihydroxypyrido-pyrazine-1,6-dione representative example.

Figure 6

The evolution of bicyclic pyrimidones.

Figure 7

The evolution of pyrrolloquinolones.

Figure 8

Docking poses of selected HIV-1 integrase inhibitors upon the 1BL3 IN crystal structure. A, MK-0518; B, S-1360; C, L870,810; D, GSK-364735; E, GS-9137; F, compound 2; G, compound 11; H, compound 16; I, compound 17; J, compound 26.