Evaluation of the Pharmacokinetic Features and Tissue Distribution of the Potent Nonnucleoside Inhibitor of HIV-1 Reverse Transcriptase, N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240) with an Analytical HPLC Method

  title={Evaluation of the Pharmacokinetic Features and Tissue Distribution of the Potent Nonnucleoside Inhibitor of HIV-1 Reverse Transcriptase, N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240) with an Analytical HPLC Method},
  author={Chun-Lin Chen and Fatih M. Uckun},
  journal={Pharmaceutical Research},
AbstractPurpose. The purpose of the present study was to examine the pharmacokinetic features and tissue distribution of N-[2-(2-fluorophenethyl)]-N′-[2-(5-bromopyridyl)]-thiourea (HI-240), a novel non-nucleoside inhibitor of HIV reverse transcriptase with potent anti-viral activity against AZT-sensitive as well as multidrug-resistant HIV-1 strains. Methods. A sensitive and accurate high performance liquid chromatography (HPLC)-based quantitative detection method was established to measure… 
In Vivo Pharmacokinetic Features, Toxicity Profile, and Chemosensitizing Activity of α-Cyano-β-hydroxy-β- methyl-N-(2,5-dibromophenyl)propenamide (LFM-A13), a Novel Antileukemic Agent Targeting Bruton’s Tyrosine Kinase
BTK inhibitors such as LFM-A13 may be useful as a new class of chemosensitizing and apoptosis-promoting antileukemic agents for treatment of patients with chemotherapy-resistant B-lineage leukemias or lymphomas.
A 13-Week Subchronic Intravaginal Toxicity Study of the Novel Broad-Spectrum Anti-HIV and Spermicidal Agent, N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (PHI-346) in Mice
Repeat intravaginal administration of PHI-346 at concentrations as high as 1,400-times its spermicidal EC50 and 2 ×107 times its in vitro anti-HIV IC50 was not associated with local or systemic toxicity and did not adversely affect the reproductive performance in mice.
Novel tight binding PETT, HEPT and DABO-based non-nucleoside inhibitors of HIV-1 reverse transcriptase
  • O. D'cruz, F. Uckun
  • Biology, Medicine
    Journal of enzyme inhibition and medicinal chemistry
  • 2006
The chemistry and biological evaluation of highly potent novel phenethylthiazolylthiourea (PETT), 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and dihydroalkoxybenzyloxopyrimidine (DABO) derivatives targeting the hydrophobic binding pocket of HIV-1 RT are described.
Effect of stereo and regiochemistry towards wild and multidrug resistant HIV-1 virus: viral potency of chiral PETT derivatives.
Experimental evidence is provided that the stereochemistry and the regiochemistry of non-nucleoside inhibitors can profoundly affect their anti-HIV activity.
Effect of stereochemistry on the anti-HIV activity of chiral thiourea compounds.
Experimental evidence is provided that the stereochemistry as well as regiochemistry of NNRTI can profoundly affect their anti-HIV activity.
Dawn of non-nucleoside inhibitor-based anti-HIV microbicides.
Structural, biological and preclinical studies relevant to the clinical development of these NNRTIs as molecular virucides intended to prevent the sexual transmission of HIV-1 are focused on.
Structural Requirements for Potent Anti-Human Immunodeficiency Virus (HIV) and Sperm-Immobilizing Activities of Cyclohexenyl Thiourea and Urea Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase1
The extremely rapid SIA of the urea analog as well as the broad-spectrum anti-HIV activity of spermicidal CHET-NNIs together with their lack of mucosal toxicity and the marked ability to reduce in vivo fertility is particularly useful for the clinical development of a dual-function s permicidal microbicide.


Pharmacokinetics and Biologic Activity of the Novel Mast Cell Inhibitor, 4-(3′-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline in Mice
WHI-P180 is an active inhibitor of IgE/antigen-induced vascular hyperpermeability in a well-characterized murine model of passive cutaneous anaphylaxis and may provide the basis for design of effective treatment and prevention programs for mast cell mediated allergic reactions.
The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection
In vivo, various triple-drug combinations of NNRTIs with NRTIs and PIs and/or PIs have been shown to afford a durable anti-HIV activity, as reflected by both a decrease in plasma HIV-1 RNA levels and increased CD4 T-lymphocyte counts.
The PETT series, a new class of potent nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase
Through an integrated effort involving synthesis and molecular modeling, compounds with nanomolar potency against HIV-1 in cell culture were developed and LY300046-HCl was identified as a potent nonnucleoside inhibitor of HIV- 1 RT possessing favorable pharmacokinetic properties.
Structure-based design of N-[2-(1-piperidinylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea and N-[2-(1-piperazinylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea as potent non-nucleoside inhibitors of HIV-1 reverse transcriptase.
Docking studies using the computer-generated model of the binding pocket suggested that the replacement of the planar pyridyl ring of trovirdine with a nonplanar piperidinyl or piperazinyl ring, which occupy larger volumes, would better fill the spacious Wing 2 region of the butterfly-shaped NNI binding pocket.
Rational design and synthesis of phenethyl-5-bromopyridyl thiourea derivatives as potent non-nucleoside inhibitors of HIV reverse transcriptase
Abstract A series of novel phenethylthiazolylthiourea (PETT) derivatives targeting the nonnucleoside inhibitor (NNI) binding site of HIV reverse transcriptase (RT) have been designed based on the
Non-nucleoside inhibitors of HIV-1 reverse transcriptase
Four years ago it became apparent that an allosteric site on HIV-1 reverse transcriptase was responsible for the enzyme inhibitory activity of a number of structurally diverse organic compounds, and these compounds proved to be potent antiviral agents.
Quantitative high-performance liquid chromatography-based detection method for calphostin C, a naturally occurring perylenequinone with potent antileukemic activity.
A sensitive and accurate high-performance liquid chromatography (HPLC)-based quantitative detection method for the measurement of calphostin C levels in plasma is established and the availability of this assay will now permit detailed pharmacodynamic and pharmacokinetic studies of cal PHOSTin C in vivo.
Tissue distribution and metabolic disposition of zidovudine in rats.
The tissue distribution and metabolic fate of [5'-3H]zidovudine was studied in rats after a single dose of 10 mg/kg by gavage, and it was found that in the testes and the brain the radioactivity was lower than in plasma, while in the heart, lung, thymus, lymph nodes, muscle, bone, and skin it was similar to that in plasma.
DMSO seems to have a relatively low order of systemic toxicity and has excellent solvent properties and other characteristics that make it a useful solvent for the administration of waterinsoluble drugs, but it should be diluted before parenteral use.
Physiological Parameters in Laboratory Animals and Humans