A novel anti-HIV active integrase inhibitor with a favorable in vitro cytochrome P450 and uridine 5′-diphospho-glucuronosyltransferase metabolism profile

Abstract

Research efforts on the human immunodeficiency virus (HIV) integrase have resulted in two approved drugs. However, co-infection of HIV with Mycobacterium tuberculosis and other microbial and viral agents has introduced added complications to this pandemic, requiring favorable drug-drug interaction profiles for antiviral therapeutics targeting HIV. Cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) are pivotal determining factors in the occurrence of adverse drug-drug interactions. For this reason, it is important that anti-HIV agents, such as integrase inhibitors, possess favorable profiles with respect to CYP and UGT. We have discovered a novel HIV integrase inhibitor (compound 1) that exhibits low nM antiviral activity against a diverse set of HIV-1 isolates, and against HIV-2 and the simian immunodeficiency virus (SIV). Compound 1 displays low in vitro cytotoxicity and its resistance and related drug susceptibility profiles are favorable. Data from in vitro studies revealed that compound 1 was not a substrate for UGT isoforms and that it was not an inhibitor or activator of key CYP isozymes.

Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor

“…Unconjugated bilirubin is highly bound to albumin and can lead to toxicities if the bilirubin/albumin molar ratio exceeds 1:1 (Zhang et al, 2005). We had noted in our earlier studies the lack of UGT substrate activity of compound 1 (Okello, et al, 2013a). In contrast, raltegravir, elvitegravir and dolutegravir are substrates and depend on UGTs for clearance.…”

“…1). Compound 1 displayed significant in vitro activity against a broad set of HIV-1 subtypes (Keele et al, 2006), as well as against HIV-2 and SIV, and with very low cell cytotoxicity (Okello et al, 2013a). In addition, this compound exhibited a positive drug susceptibility profile against some key clinically-relevant integrase mutations (Fig.…”

A novel molecule with notable activity against multi-drug resistant tuberculosis

“…Compound 2 appears to seek out the Mg 2+ ion in the β′-subunit for chelating and it also binds to amino acid residues, many of which are similar to those involved in the binding of inhibitor 1 to the active site of HIV-1 integrase. 21 Further studies are in progress to lend support to this proposed mechanism of action. Interestingly, compound 2 also displayed activity against HIV-1 in MAGI-R5 cells with an EC 50 of 50 ± 10 nM, suggesting the potential for dual therapeutic applications of this compound.…”

“…21 Compound 1 displayed significant in vitro activity against a broad set of HIV-1 subtypes, as well as against HIV-2 and SIV, and with very low cell cytotoxicity. 21 In addition, this compound exhibited a positive drug susceptibility profile against some key clinically-relevant integrase mutations. The in vivo pharmacokinetic and toxicokinetic data were also compelling.…”

“…The focus of this communication will be on compound 2 , which has the following structural properties: a high cLogP (6.3) for cell wall and cell membrane entry; a suitable 3D polar surface area (84 Å 2 ); appropriate numbers of hydrogen bond accepting and donating groups (7 and 1, respectively) for interaction with amino acid residues in the ligand binding site; a pKa of 9, which is in the range of some key anti-MDR TB compounds; a high number of rotatable bonds (10); the presence of an enolic-keto functional group capable of binding to Mg 2+ ; and a heterocyclic scaffold discovered earlier by us to be critical for anti-retroviral activity. 21,22 …”