Delavirdine

Delavirdine

Clinical data
Trade names	Rescriptor
AHFS/Drugs.com	Monograph
MedlinePlus	a600034
Pregnancy category	AU:B3
Routes of administration	By mouth
ATC code	J05AG02 ( WHO )
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	85%
Protein binding	98%
Metabolism	Liver (CYP3A4- and CYP2D6-mediated)
Elimination half-life	5.8 hours
Excretion	Kidney (51%) and feces (44%)
Identifiers
IUPAC name N-[2-({4-[3-(propan-2-ylamino)pyridin-2-yl]piperazin-1-yl}carbonyl)-1H-indol-5-yl]methanesulfonamide
CAS Number	136817-59-9  Y
PubChem CID	5625
DrugBank	DB00705  Y
ChemSpider	5423  Y
UNII	DOL5F9JD3E
KEGG	D07782  Y
ChEBI	CHEBI:119573  Y
ChEMBL	ChEMBL593  Y
NIAID ChemDB	005059
PDB ligand	SPP ( PDBe , RCSB PDB )
CompTox Dashboard (EPA)	DTXSID6022892
Chemical and physical data
Formula	C22H28N6O3S
Molar mass	456.57 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC(C)Nc1cccnc1N4CCN(C(=O)c3cc2cc(NS(C)(=O)=O)ccc2[nH]3)CC4
InChI InChI=1S/C22H28N6O3S/c1-15(2)24-19-5-4-8-23-21(19)27-9-11-28(12-10-27)22(29)20-14-16-13-17(26-32(3,30)31)6-7-18(16)25-20/h4-8,13-15,24-26H,9-12H2,1-3H3 Y Key:WHBIGIKBNXZKFE-UHFFFAOYSA-N Y
(verify)

Delavirdine (DLV) (brand name Rescriptor) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that was marketed by ViiV Healthcare. It was used as part of highly active antiretroviral therapy (HAART) for the treatment of HIV-1 in the late 1990s and early 2000s. It is presented as the mesylate. The recommended dosage is 400 mg (as four 100-mg tablets or two 200-mg tablets) three times a day.

Although delavirdine was approved by the U.S. Food and Drug Administration in 1997, its efficacy was found to be lower than other NNRTIs, especially efavirenz, and it also had an inconvenient dosing schedule. These factors have led the U.S. DHHS not to recommend its use as part of initial therapy. ^[1] The risk of cross-resistance across the NNRTI class, as well as its complex set of drug interactions, made the place of delavirdine in second-line and salvage therapy unclear, and it was very rarely used.

As of 2018, its manufacturing and distribution was discontinued in the United States and Canada. ^{[2] [3] [4]} It has not been used in other countries.

Interactions

Like ritonavir, delavirdine is an inhibitor of cytochrome P450 isozyme CYP3A4, and interacts with many medications. It should not be administered with a wide range of drugs, including amprenavir, fosamprenavir, simvastatin, lovastatin, rifampin, rifabutin, rifapentine, St John's wort, midazolam, triazolam, ergot medications, and several medications for acid reflux. ^[1]

Adverse effects

The most common adverse event is moderate to severe rash, which occurs in up to 20% of patients. ^[5] Other common adverse events include fatigue, headache and nausea. Liver toxicity has also been reported.

Synthesis

Delavirdine synthesis:

Modification of the scheme that was done for ateviridine q.v. by performing the reductive alkylation with acetone gives 2 after removal of the protecting group. Acylation of this amine with the imidazolide from 5-Methylsulfonaminoindole-2-carboxylic acid (1) affords the amide, reverse transcriptase inhibitor, atevirdine.

References

1. DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (4 May 2006). (Available for download from AIDSInfo Archived 6 May 2006 at the Wayback Machine )
2. RPh DE (11 May 2017). "HIV Drug Soon to Be Unavailable". MPR.
3. "Delavirdine: Indications, Side Effects, Warnings". Drugs.com.
4. "Prescription drug RESCRIPTOR (delavirdine mesylate) – DrugFinder.ca". drugfinder.ca.
5. "RESCRIPTOR brand of delavirdine mesylate tablets. Product information" (PDF). Archived from the original (PDF) on 15 April 2006. Retrieved 18 May 2006.
6. WO 9109849,Romero DL, Mitchell MA, Thomas RC, Palmer JR, Tarpley WG, Aristoff PA, Smith HW,"Diaromatic Substituted Anti-AIDS Compounds",published 11 July 1991, assigned to Upjohn Company 
7. US 5563142,Palmer JR, Romero DL, Aristoff PA, Thomas RC, Smith HW,"Diaromatic substituted compounds as anti-HIV-1 agents",published 8 October 1996, assigned to Upjohn Company 
8. Romero DL, Morge RA, Genin MJ, Biles C, Busso M, Resnick L, et al. (May 1993). "Bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: structure-activity relationships of novel substituted indole analogues and the identification of 1-[(5-methanesulfonamido-1H-indol-2-yl)-carbonyl]-4-[3- [(1-methylethyl)amino]-pyridinyl]piperazine monomethanesulfonate (U-90152S), a second-generation clinical candidate". Journal of Medicinal Chemistry. 36 (10): 1505–8. doi:10.1021/jm00062a027. PMID   7684450.