Stampidine

Stampidine
Skeletal formula of stampidine
Ball-and-stick model of the stampidine molecule
Clinical data
ATC code
  • none
Identifiers
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
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC20H23BrN3O8P
Molar mass544.295 g·mol−1
3D model (JSmol)
SMILES
  • Cc1cn(c(=O)[nH]c1=O)[C@H]2C=C[C@H](O2)COP(=O)(N[C@H](C)C(=O)OC)Oc3ccc(cc3)Br
InChI
  • InChI=1S/C20H23BrN3O8P/c1-12-10-24(20(27)22-18(12)25)17-9-8-16(31-17)11-30-33(28,23-13(2)19(26)29-3)32-15-6-4-14(21)5-7-15/h4-10,13,16-17H,11H2,1-3H3,(H,23,28)(H,22,25,27)/t13-,16+,17-,33?/m1/s1
  • Key:VPABMVYNSQRPBD-AOJMVMDXSA-N
  (verify)

Stampidine is an experimental nucleoside reverse transcriptase inhibitor (NRTI) with anti-HIV activity.[1][2]

It is a derivative of stavudine (d4T, brand name 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

Stampidine exhibited:

  • 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,
  • favorable safety profile in mice, rats, dogs, and cats, and
  • promising prophylactic in vivo antiretroviral activity in Hu-PBL-SCID mice as well as therapeutic anti-retroviral activity in FIV-infected domestic cats.

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 antiretroviral 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.

References

  1. 1 2 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. S2CID 8037238.
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