Stampidine

Stampidine

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	217178-62-6  Y
PubChem CID	469782
ChemSpider	412689
UNII	MHN9I3MQ1X
CompTox Dashboard (EPA)	DTXSID80944332
Chemical and physical data
Formula	C20H23BrN3O8P
Molar mass	544.295 g·mol−1
3D model (JSmol)	Interactive image
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
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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. 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. S2CID   37628532.
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.