Potent and selective inhibitors of human immunodeficiency virus protease structurally related to L-694,746 (original) (raw)
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Design and synthesis of inhibitors for the HIV-1 protease
1994
A variety of phosphonamidate-containing peptides were synthesised as potential inhibitors of the HIV-1 protease. These transition state analogues were designed using known sequences from HIV-1 protease substrates and incorporated a unique Phe-Pro scissile bond mimic in an attempt to achieve selectivity over the mammalian aspartic proteases. Such compounds were found to be moderate inhibitors of the HiV-1 protease possessing iCgo values in the 1-100 pM range, both in in vitro and in vivo assays. However, the phosphonamidate methyl ester analogues showed a marked ability to enter ceils and this feature was highlighted in the 1:1 ratio of in vivo/ in vitro iCso values (generally for peptidic inhibitors, this ratio is 10-10000 fold higher, indicating poor cell uptake properties). Optimisation of the methyl ester analogues was attempted by alteration of the binding residues flanking either side of the phosphonamidate moiety. However, such alterations had only a small effect on inhibitor ...
Novel inhibitors of HIV protease
Bioorganic & Medicinal Chemistry Letters, 2000
novel series of HIV protease inhibitors containing cyclic P1/P2 scaolds has been synthesized and evaluated for biological activity. The trans 3,5-dibenzyl-2-oxo pyrrolidinone ring system resulted in a 50 pM enzyme inhibitor against HIV protease in vitro when combined with an indanolamine derived P H-backbone. This compound also shows comparable activity to currently marketed drugs in the MT-4 cell-based antiviral assay.
Journal of Medicinal Chemistry, 1995
Using molecular modeling and the information derived from the X-ray crystal structure of HIV-1 protease (HIV PR) complexed with the pyran-2-one 1, a series of (4-hydroxy-6-phenyl-2-oxo-W-pyran-3-yl)thiomethanes was designed and analyzed as novel, nonpeptidic inhibitors of HIV PR. Structure-activity studies led to the discovery of inhibitor 19 having (RS)-1-(cyclopentylthio)-3-methylbutyl functionalization at the C-3 position, which exhibited a K, of 33 nM. A X-ray crystallographic structure of 19 bound to HIV PR showed that structural water-301 (inhibitor-flap-bridging water) was displaced by the inhibitor. Interestingly, the enol moiety of the pyran-2-one formed a hydrogen bond directly with Asp125 and with Asp25 via a bridging water molecule, thus illustrating a unique mode of active site binding by a n HIV PR inhibitor. The pendant cyclopentyl and isobutyl groups of 19 occupied the SI' and SZ' binding sites, respectively, whereas the 6-phenyl group occupied a region in between the SI and SS pockets of HIV PR. Selected compounds were tested for antiviral activity on H9 cells infected with HIV-lIIIb. A correlation between enzymatic activity and antiviral activity was not found in this series. The best antiviral compound in this series, 18, contained (RS)-3-[cyclopentyl(cyclopentylthio)methyll functionalization at the C-3 position of the pyran-2-one ring and exhibited a C I C~O of 14 pM and TC50 of 70 pM. These studies demonstrate that potent enzyme inhibition can be achieved by inhibitors that span only three subsites.
Bioorganic & Medicinal Chemistry, 1999
ÐThe structure±activity relationship of HIV-1 protease (HIV-1 PR) inhibitors containing a-hydroxy-b-amino acids is discussed. We demonstrated that substituent groups on the P 1 aromatic rings of the inhibitors exert signi®cant in¯uence on their biological activity. Inhibitors bearing an alkyl or a¯uorine atom at the meta and para position on their P 1 benzene ring were found to be good inhibitors. We also discovered that the substitution positions of the P 2 benzamides were crucial for good antiviral potency. In this study, inhibitor 48 was the most potent {IC 90 (CEM/HIV-1 IIIB) 27 nM} and showed good pharmacokinetics in rats.
Bioorganic & Medicinal Chemistry, 2003
A series of novel HIV-1 protease inhibitors based on two pseudosymmetric dipeptide isosteres have been synthesized and evaluated. The inhibitors were designed by incorporating Nphenyloxazolidinone-5-carboxamides into the hydroxyethylene and (hydroxyethyl)hydrazine dipeptide isosteres as P2 and P2′ ligands. Compounds with (S)-phenyloxazolidinones attached at a position proximal to the central hydroxyl group showed low nM inhibitory activities against wildtype HIV-1 protease. Selected compounds were further evaluated for their inhibitory activities against a panel of multidrug-resistant protease variants and for their antiviral potencies in MT-4 cells. The crystal structures of lopinavir (LPV) and two new inhibitors containing phenyloxazolidinone-based ligands in complex with wild-type HIV-1 protease have been determined. A comparison of the inhibitor-protease structures with the LPV-protease structure provides valuable insight into the binding mode of the new inhibitors to the protease enzyme. Based on the crystal structures and knowledge of structure-activity relationships, new inhibitors can be designed with enhanced enzyme inhibitory and antiviral potencies.
Journal of Medicinal Chemistry, 1996
A series of novel aminodiol inhibitors of HIV protease based on the lead compound 1 with structural modifications at P 1 ′ were synthesized in order to reduce the cytotoxicity of 1. We have observed a high degree of correlation between the lipophilicity and the cytotoxicity of this series of inhibitors. It was found that appropriate substitution at the para position of the P 1 ′ phenyl group of 1 resulted in the identification of equipotent (both against the enzyme and in cell culture) compounds (10l, 10m, 10n, and 15c) which possess significantly decreased cytotoxicity.
Bioorganic & Medicinal Chemistry, 2006
As a continuation of the recently communicated discovery of oximinoarylsulfonamides as potent inhibitors of HIV-1 aspartyl protease, compounds bearing pyridylmethyl substituents at P3 were designed and synthesized. Potent analogs in this series provided low single-digit nanomolar EC 50 values against both wild-type HIV and resistant mutant virus (A17), attenuated some 3-to 12-fold in the presence of 50% human serum. Pharmacokinetic results for compounds in this series showed good to excellent exposure when co-administered orally with an equal amount of ritonavir (5 mg/kg each) in the rat, with average AUC >8 lg h/mL. Similar dosing in dog resulted in significantly lower plasma levels (average AUC <2 lg h/mL). The 3-pyridylmethyl analog 30 gave the best overall exposure (rat AUC = 7.1 lg h/mL and dog AUC = 4.9 lg h/mL), however, this compound was found to be a potent inhibitor of cytochrome P450 3A (K i = 2.4 nM).