Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-689,502, N-[2(R)-hydroxy-1(S)-indanyl]-5(S)-(1,1-dimethylethoxy- carbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-(4-[2-(4- morpholinyl)ethoxy]phenyl)methyl hexanamide, is a potent inhibitor of human immunodeficiency virus-1 protease. The effect of dose on the elimination kinetics of L-689,502 was studied in rats and dogs. After i.v. administration, total plasma clearance of L-689,502 in rats decreased with increasing dose; the clearance decreased from 181 ml/min/kg at 1 mg/kg to 86 ml/min/kg at 20 mg/kg. Similar results were observed in dogs; clearance fell from 29 ml/min/kg at 0.5 mg/kg to 17 ml/min/kg at 10 mg/kg. Bile flow in rats was retarded in a dose-dependent manner after a single i.v. injection of L-689,502. The cholestatic effect was reversible and maximal at 5 mg/kg i.v. Consistent with the cholestatic effect, L-689,502 caused an increase in serum levels of aminotransferase. After i.v. administration of L-689,502 (10 mg/kg), alanine aminotransferase increased from 50 to 370 IU/liter and aspartate aminotransferase from 120 to 700 IU/liter. Moreover, pretreatment of rats with L-689,502 resulted in a significant decrease in the elimination kinetics of antipyrine and diflunisal, as well as of L-689,502 itself. Collectively, these results suggest that the dose-dependent kinetics of L-689,502 in rats and dogs are more likely due to hepatotoxicity caused by the drug than to capacity-limited metabolism.
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PMID:Dose-dependent toxicokinetics of L-689,502, a potent human immunodeficiency virus protease inhibitor, in rats and dogs. 140 75

Bellenamine, (R)-3,6-diamino-N-(aminomethyl)hexanamide (molecular weight 174), produced by Streptomyces nashvillensis, which has been reported to have weak antibacterial activity and to slightly enhance the immune response, showed potent activity against human immunodeficiency virus type 1 (HIV-1). Its mode of action was investigated. Bellenamine inhibited de novo infection of human T cells with HIV-1, at a 50% effective concentration (EC50) of 0.62 micrograms/ml (3.6 microM). Its 50% cytotoxic concentration (CC50) was over 2000 micrograms/ml (11.5 mM) and thus its cytotoxicity was quite low. When HIV-1-infected cells were treated with bellenamine or glycosylation inhibitors, they produced virus with reduced infectivity, and thus bellenamine inhibited the secondary spread of HIV-1 in vitro similarly to glycosylation inhibitors. However, bellenamine did not change the apparent molecular weights of env or gag proteins, unlike glycosylation inhibitors. Bellenamine showed no significant activity against virus adsorption, reverse transcriptase, viral protease or the glycosylation process. The antiviral mechanism of bellenamine remains to be examined further.
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PMID:Inhibition of human immunodeficiency virus type 1 infectivity by a new amine bellenamine. 873 96

A series of human immunodeficiency virus (HIV) protease inhibitors, which are analogues of N-[2(R)-hydroxy-1(S)- indanyl]-5(S)-[(tert-butyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-(R) - [[4-(carboxymethoxy)phenyl]methyl]hexanamide (L-694,746), a metabolite of the anti-HIV agent L-689,502, were synthesized. In these compounds, the acetic group linked to the para position of the P1' phenyl in the reference inhibitor was replaced either by the bioisosteric phosphonomethoxy group and its diisopropyl/dibenzyl derivatives, or the 1H-tetrazol-5-yl-methoxy group and its 1-benzyl derivative. In enzyme assays, phosphonomethoxy and tetrazolmethoxy analogues proved to be potent inhibitors of the HIV-1 protease, with IC50 values as low as 0.04 nM. When tested for anti-HIV-1 activity in cell-based assays, most of the new derivatives proved active, with benzyl derivatives being more active than their highly polar, unsubstituted counterparts. The dibenzylphosphonomethoxy analogue was the most active compound, with an EC50 value of 10 nM and a selectivity index of 20,000. When compounds were examined for their capability to reduce p24 levels in both acutely and chronically infected MT-4 and H9/IIIB cells, all of them were found to be active at concentrations close to those capable of preventing HIV-1-induced cytopathic effect.
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PMID:Potent and selective inhibitors of human immunodeficiency virus protease structurally related to L-694,746. 987 9