Identification of MK-944a:  A Second Clinical Candidate from the Hydroxylaminepentanamide Isostere Series of HIV Protease Inhibitors

Abstract

Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.

Looking at the proteases from a simple perspective

“…The use of these molecules has been associated with a drastic reduction in AIDS morbidity and mortality, mainly with the introduction of several HIV protease inhibitors on the therapeutic intervention of AIDS (Palella et al, 2003;Fear et al 2007;Tan et al, 2010;Wensing et al, 2010). Currently, there are nine protease inhibitors in clinical use: saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, darunavir e tipranavir (Roberts et al, 1990;Dorsey et al, 1994;Kim et al, 1995;Kaldor et al 1997;Sham et al, 1998;Turner et al, 1998;Robinson et al, 2000;Brower et al, 2008; Figure 3). These inhibitors present low oral bioavailability and short plasma half-life (Barry et al 1997;Bouzide et al, 2005, Castro et al, 2006.…”

“…Currently, there are eight protease inhibitors in clinical use: (a) ritonavir (Brower et al, 2008); (b) saquinavir (Roberts et al, 1990); (c) nelfinavir (Kaldor et al, 1997); (d) indinavir (Dorsey et al, 1994); (e) amprenavir (Kim et al, 1995); (f ) atazanavir (Robinson et al, 2000); (g) lopinavir (Sham et al, 1998); and (h) tipranavir, one protease inhibitor currently under development (Turner et al, 1998; Figure 3).…”

Ginkgolic acid inhibits HIV protease activity and HIV infection in vitro

“…Since the existing PIs target the active site of HIV protease and have similar structures, most of the drug-resistant HIV proteases confer cross-resistance to multiple PIs. There is a great need for second-generation PIs with different chemical structures and/or with an alternative mode of inhibition [8,9]. In addition, reduced general toxicity may be achieved.…”

“…For example, some natural herbal substances have been shown to be effective at inhibiting the growth of HIV in vitro at different stages in HIV-1 replication [10,11]. Collins et al [8] reported that 6 out of 19 aqueous herbal extracts significantly inhibited the interaction between HIV-1 gp120 and immobilized CD4 receptors. Several extracts have also been shown to be capable of inhibiting the activity of recombinant HIV-1 protease [12,13].…”

The Efficacy of Conceptual DFT Descriptors and Docking Scores on the QSAR Models of HIV Protease Inhibitors

“…Wilkerson et al synthesized and evaluated a series of nonsymmetrically substituted cyclic ureacarboxamides (S8) for the inhibition of HIV-proteases [13]. Dorsey et al presented the 3-pyridylmethyl-hydroxylaminpentenamides (S9) as a clinical backup of the most widely prescribed HIV protease inhibitor called indinavir [14]. Various structure and shape based attempts to design novel HIV protease inhibitors have been appeared in the literature [15].…”