Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1

Abstract

An assay recapitulating the 3' processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/aa125 variants of IN. The importance of the C7 position on the serum shifted potency was established. Introduction of a quinoline substituent at the C4 position provided a balance of potency and metabolic stability. Combination of these findings ultimately led to the discovery of compound 26 (BI 224436), the first NCINI to advance into a phase Ia clinical trial.

Keywords: HIV Integrase; LTR DNA 3′-processing; NCINI; allosteric inhibitor.

Figure 1

Ribbon representation of the superposition of compounds 11 and 16 bound to the CCD of IN, including a semitransparent surface of the CCD (PDB accession code 4NYF). The tube representations of 11 and 16 are colored by atom type, where cyan = carbon for 11, yellow = carbon for 16, blue = nitrogen, red = oxygen, green = chlorine, and maroon = bromine.

Chart 1. Evolution of the C4-Arene

Figure 2

Effect of C7 substitution on serum shift for compounds with substructure 25. (A) Box plot (N = 47 compounds) showing difference in serum shift for compounds with or without R7 substituents. (B) Scatter plot of ssEC₅₀ vs EC₅₀ (nM) for the same 47 compounds). Determined using recombinant NL4.3 virus (T124A IN mutant).