2-Amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1.

A series of 2-amino-5-arylthiobenzonitriles (1) was found to be active against HIV-1. Structural modifications led to the sulfoxides (2) and sulfones (3). The sulfoxides generally showed antiviral activity against HIV-1 similar to that of 1. The sulfones, however, were the most potent series of analogues, a number having activity against HIV-1 in the nanomolar range. Structural-activity relationship (SAR) studies suggested that a meta substituent, particularly a meta methyl substituent, invariably increased antiviral activities. However, optimal antiviral activities were manifested by compounds where both meta groups in the arylsulfonyl moiety were substituted and one of the substituents was a methyl group. Such a disubstitution led to compounds 3v, 3w, 3x, and 3y having IC50 values against HIV-1 in the low nanomolar range. When gauged for their broad-spectrum antiviral activity against key non-nucleoside reverse transcriptase inhibitor (NNRTI) related mutants, all the di-meta-substituted sulfones 3u-z and the 2-naphthyl analogue 3ee generally showed single-digit nanomolar activity against the V106A and P236L strains and submicromolar to low nanomolar activity against strains E138K, V108I, and Y188C. However, they showed a lack of activity against the K103N and Y181C mutant viruses. The elucidation of the X-ray crystal structure of the complex of 3v (739W94) in HIV-1 reverse transcriptase showed an overlap in the binding domain when compared with the complex of nevirapine in HIV-1 reverse transcriptase. The X-ray structure allowed for the rationalization of SAR data and potencies of the compounds against the mutants.

Novel inhibitors of HIV protease: design, synthesis and biological evaluation of picomolar inhibitors containing cyclic P1/P2 scaffolds.

A novel series of HIV protease inhibitors containing cyclic P1/P2 scaffolds 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'-backbone. This compound also shows comparable activity to currently marketed drugs in the MT-4 cell-based antiviral assay.

Inhibitors of human immunodeficiency virus type 1 derived from gp41 transmembrane protein: structure--activity studies.

We synthesized analogues of gp41 (553-590), 1, and evaluated them for their inhibitory activity against HIV-1 in MT4 cell assay (IC50(1) = 2.7 microM). (The numbering scheme for gp41 (e.g., gp41(553-590) for 1) adapted throughout the text is from ref 6.) Gradual truncation of either the N- or C-terminal end of gp41 (553-590) resulted in a substantial loss of inhibitory properties of resulting compounds. Unexpectedly, simultaneous truncations of both N- and C-termini of gp41(553-590) resulted in a potent heptadecamer, 13, IC50 = 10.4 microM. Coupling of a racemic alpha-aminotetradecanoic acid (Atd) to gp41 fragments afforded diastereomeric conjugates, most of which were chromatographically separable. In this series, pentadecamer 27 had an IC50 of 8.9 microM, while its Atd diastereomer 28 was much less inhibitory. This finding is consistent with relative inhibitory potencies of other Atd-containing diastereomeric pairs and could reflect a chiral sense of Atd residue interacting with the receptor. Compounds 13 and 27, which are practically equipotent to 1, represent minimalistic fragments of the leucine-zipper region of gp41 and constitute a basis for design of a second generation of gp41-based inhibitors. Circular dichroism studies suggested that compounds in this series are likely to inhibit HIV-1 replication by virtue of their alpha-helical character. The observed structure-activity relationship supports impairment of viral gp41 as a possible mechanism of action of 1.

Antiviral, metabolic, and pharmacokinetic properties of the isomeric dideoxynucleoside 4(S)-(6-amino-9H-purin-9-yl)tetrahydro-2(S)-furanmethanol.

4(S)-(6-Amino-9H-purin-9-yl)tetrahydro-2(S)-furanmethanol (IsoddA) is the most antivirally active member of a novel class of optically active isomeric dideoxynucleosides in which the base has been transposed from the natural 1' position to the 2' position and the absolute configuration is (S,S). IsoddA was active against human immunodeficiency virus type 1 (HIV-1) (strain IIIB), HIV-2 (strain ZY), and HIV-1 clinical isolates. Combinations of the compound with zidovudine (3'-azido-3'-deoxythymidine), 2',3'-dideoxyinosine, or 5-fluoro-2'-deoxy-3'-thiacytidine showed synergistic inhibition of HIV. A moderate reduction of activity was observed with clinical isolates resistant to zidovudine. An IsoddA-resistant virus (eightfold-increased 50% inhibitory concentration) was selected in vitro by repeated passage of HIV-1 (HXB2) in the presence of increasing concentrations of IsoddA. The reverse transcriptase-coding region of the mutant virus contained a single base change resulting in a change at codon 184 from Met to Val. IsoddA was also active against hepatitis B virus (HBV) in vitro; however, it lacked substantial selective activity in an in vivo HBV model. IsoddA was inefficiently phosphorylated in CEM cells; however, the half-life of the triphosphate was 9.4 h, and IsoddATP was a potent inhibitor of HIV-1 reverse transcriptase, with a Ki of 16 nM. The cytotoxicity 50% inhibitory concentrations of IsoddA were greater than 100 microM for CEM, MOLT-4, IM9, and the HepG2-derived HBV-infected 2.2.15 (subclone P5A) cell lines but were 12 and 11 microM for human granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) progenitor cells, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Sodium azide protects against ischemia-induced acute renal failure in rats.

Sodium azide (AZ) is a nitrovasodilator with diverse biochemical properties. We found that low doses of AZ led to a profound protective effect against postischemic, acute renal failure (ARF) in rats. AZ, given at 250 micrograms/kg iv, before 25 min of renal artery occlusion (RAO) and again before reperfusion, conferred almost complete protection against loss of kidney function determined 18 h after RAO. The effect of AZ was evidenced by a higher creatinine clearance (+348%) and lower levels of blood urea nitrogen (-69%) and histological renal damage (-50%) compared with ischemic control animals. Indexes of kidney function in AZ-treated animals subjected to RAO were not significantly different from those of nonischemic control animals. Two other nitrovasodilators, sodium nitroprusside and hydralazine, at doses which produced decreases in blood pressure similar to that of AZ, were ineffective at preventing ARF. The beneficial effect of AZ may be due to its known ability to inhibit one or more enzymes including adenosinetriphosphatase, cytochrome-c oxidase, and myeloperoxidase.

Trifenagrel: a chemically novel platelet aggregation inhibitor.

Trifenagrel.HCl (trifenagrel) (2-[2-(2-dimethylaminoethoxy) phenyl]-4,5-diphenylimidazole monohydrochloride) is a chemically novel, potent inhibitor (IC50 = 0.3-3.0 microM) of arachidonate (AA)- and collagen-induced aggregation of platelets from several animal species and humans. When trifenagrel was administered p.o. to guinea pigs, there was a sustained (greater than 3 hr) inhibition of AA- and collagen-induced platelet aggregation ex vivo (1 hr ED50 = 1.4 and 9.4 mg/kg, respectively). In humans, trifenagrel inhibited the second phase of ADP-induced aggregation ex vivo up to 6 hr after a single dose of 100 to 300 mg p.o. The mechanism of action of trifenagrel appears to be a reversible inhibition of platelet AA cyclooxygenase. Doses of trifenagrel up to 100 mg/kg p.o. in rats and guinea pigs inhibited gastric mucosal AA cyclooxygenase but did not produce the gastric damage associated with the administration of other cyclooxygenase inhibitors such as aspirin and indomethacin. To our knowledge this is the first report of a compound which inhibits gastric mucosal prostaglandin levels but causes little or no gastrointestinal (g.i.) irritation in rodents. Although trifenagrel caused g.i. irritation in dogs and humans, the nature of the damage suggests that the compound may have acted as a local irritant in these species. Furthermore, compared to aspirin trifenagrel produced significantly less gastric irritation and fecal blood loss in humans. The physiochemical properties of trifenagrel may be important for the lack of g.i. irritation in rodents and for the diminished damage relative to aspirin in humans.