Stampidine

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Stampidine
Stampidine.svg
Systematic (IUPAC) name
methyl N-((4-bromophenoxy){[(2S,5R)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl]methoxy}phosphoryl)-D-alaninate
Clinical data
Legal status ?
Identifiers
ATC code None
PubChem CID 469782
Chemical data
Formula C20H23BrN3O8P 
Mol. mass 544.289 g/mol
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Stampidine is an experimental nucleoside reverse transcriptase inhibitor (NRTI) with anti HIV activity.[1][2]

It is a derivative of d4T (stavudine, Zerit), and has been designed to avoid dependence on the rate limiting step of phosphorylation of stavudine to stavudine monophosphate. This is governed by the supply of thymidine kinase that is available, and stavudine is poorly phosphorylated to its monophosphate form in thymidine kinase-deficient cells.[1]

Preclinical pharmacology[edit]

Stampidine exhibited (a) subnanomolar to low nanomolar in vitro antiretroviral potency against genotypically and phenotypically NRTI-resistant primary clinical HIV isolates, non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 isolates, clinical non-B subtype HIV-1 isolates (subtypes A, C, F, and G) originating from South America, Asia, and sub-Saharan Africa with resistance to stavudine, adefovir and tenofovir, as well as recombinant HIV clones containing common patterns of RT mutations responsible for NRTI resistance such as multiple TAMs plus M184V, multiple TAMs plus T69 insertion, and Q151 complex (b) favorable, safety profile in mice, rats, dogs, and cats, and (c) promising prophylactic in vivo anti-retroviral activity in Hu-PBL-SCID mice as well as therapeutic anti-retroviral activity in FIV-infected domestic cats.

Stampidine results in methylation of a network of HIV-responsive regulatory genes in T-cells, including several genes for HIV-dependency factors (HDFs).[3] Stampidine epigenetically modulates the host transcriptome in a unique manner, silences expression of a distinct set of genes encoding transcription factors and signal transduction molecules, and prevents HIV infection from distorting and disrupting key cellular transcriptional networks. At nanomolar concentrations that are 4-logs lower than those achieved at its non-toxic dose levels in mice, rats, cats, and dogs, Stampidine switched off genes for several HDFs that are required for HIV replication in T-cells. Notably, Stampidine reversed the effects of HIV exposure on the host transcriptome regardless of NRTI-sensitivity or RT mutations of the HIV isolate used and inhibited the replication of 17 NRTI-resistant HIV-1 strains, including recombinant HIV clones containing common patterns of RT mutations responsible for NRTI resistance, in human peripheral blood mononuclear cells (PBMC) with subnanomolar-nanomolar IC50 values. Unlike available ARV agents that disrupt a specific step in the life-cycle of HIV, Stampidine has the potential to abrogate all steps in the life cycle of HIV.

Clinical trials[edit]

In a placebo-controlled Phase I study involving 30 therapy-naïve adult HIV-infected adult patients, formulated GMP-grade oral Stampidine capsules did not cause dose-limiting toxicity at single dose levels ranging from 5 to 25 mg/kg.[4]

References[edit]

  1. ^ a b Uckun FM (February 2006). "Stampidine as a novel nucleoside reverse transcriptase inhibit with potent anti-HIV activity". Arzneimittelforschung 56 (2A): 121–35. doi:10.1055/s-0031-1296800. PMID 16570821. 
  2. ^ Uckun FM, Cahn P, Qazi S, D'Cruz O (April 2012). "Stampidine as a promising antiretroviral drug candidate for pre-exposure prophylaxis against sexually transmitted HIV/AIDS". Expert Opin Investig Drugs 21 (4): 489–500. doi:10.1517/13543784.2012.664635. PMID 22360744. 
  3. ^ Qazi S, Uckun F (2012). "Stampidine as a Potent Epigenetic Silencer of Host HIV Dependency Factor Genes in HIV-Infected Cells". Journal of AIDS & Clinical Research 3: 64. doi:10.4172/2155-6113.1000147. 
  4. ^ Cahn P, Rolon MJ, Gun AM, Ferrari I, Dibirdik I, Qazi S, D'Cruz O, Sahin K, Uckun F (2012). "Preclinical and First-In-Human Phase I Clinical Evaluation of Stampidine, a Potent Anti-HIV Pharmaceutical Drug Candidate". Journal of AIDS & Clinical Research 3: 1. doi:10.4172/2155-6113.1000138.