MK-2048

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MK-2048
MK-2048.svg
MK-2048
Clinical data
ATC code
  • none
Legal status
Legal status
Identifiers
  • (6S)-2-[(3-chloro-4-fluorophenyl)methyl]-8-ethyl-9-hydroxy-N,6-dimethyl-1,10-dioxo-6,7-dihydropyrazino[3,4]pyrrolo[3,4-b]pyridazine-4-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.233.568 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H21ClFN5O4
Molar mass 461.88 g·mol−1
3D model (JSmol)
  • CCN1CC(N2C3=C(C(=O)C2=C1O)C(=O)N(N=C3C(=O)NC)CC4=CC(=C(C=C4)F)Cl)C
  • InChI=1S/C21H21ClFN5O4/c1-4-26-8-10(2)28-16-14(18(29)17(28)21(26)32)20(31)27(25-15(16)19(30)24-3)9-11-5-6-13(23)12(22)7-11/h5-7,10,32H,4,8-9H2,1-3H3,(H,24,30)/t10-/m0/s1
  • Key:IOYLKNABOQYKKY-JTQLQIEISA-N

MK-2048 is a drug that was investigated for the prevention of HIV infection. The drug failed to show a difference in treatment and control arms in Phase I trials. No further studies are planned.

Contents

Design and pre-clinical trials

MK-2048 is an integrase inhibitor designed to prevent the integration of the HIV virus into the genome of the host cells. [1] MK-2048 is considered a "second generation integrase". The drug was designed to increase the putative half-life of the drug in the system and therefore increase its potential efficacy as well as avoid resistance to the first line integrase inhibitors. [1] [2] [3] In pre-clinical tests, MK-2048 was as effective against the HIV integrase mutant N155H as against wild-type virus. This class of drugs were designed to be delivered by Vaginal ring to be inserted before sexual intercourse. As such, MK-2048 was investigated for use as part of a pre-exposure prophylaxis (PrEP) approach to the treatment of HIV infection. [4]

Clinical trials

The first clinical trial was completed in 2016 and tested the safety and pharmacokinetics of MK-2048 and Vicriviroc (VCV or MK-4176) as delivered by vaginal rings (VR). [5] The single-blind, randomized, placebo-controlled trial was conducted in 48 women, evaluated VRs containing MK-2048 (30 mg) and vicriviroc (VCV, 182 mg), alone or in combination, and placebo. The ring was used continuously for 28 days. The VR with drug reported no more adverse effects than the placebo. There was also no difference in HIV infection acquisition in the control and treatment arms despite high levels of drug in the tissues.

References

  1. 1 2 Mascolini M (April 2009). Conference Reports for NATAP: Merck Offers Unique Perspective on Second-Generation Integrase Inhibitor. 10th International Workshop on Clinical Pharmacology of HIV Therapy. Amsterdam]: NATAP.org. Archived from the original on June 4, 2017. Retrieved November 8, 2009.
  2. ↑ Grobler JA, McKenna PM, Ly S, Stillmock K, Bahnck C, Danovich RM, et al. (April 2009). Presentation, Abstract O-10: Functionally Irreversible Inhibition of Integration by Slowly Dissociating Strand Transfer Inhibitors. 10th International Workshop on Clinical Pharmacology of HIV Therapy. Amsterdam]: NATAP.org.
  3. ↑ Bar-Magen, T; Sloan, RD; Donahue, DA; Kuhl, BD; Zabeida, A; Xu, H; Oliveira, M; Hazuda, DJ; Wainberg, MA (2010). "Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor". J Virol. 84 (18): 9210–9216. doi:10.1128/JVI.01164-10. PMC   2937597 . PMID   20610719.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ↑ Alcorn K (April 28, 2009). "Ralvetgravir Shows Potential for use as PrEP Drug". AIDSmap.com. Archived from the original on January 3, 2010. Retrieved November 8, 2009.
  5. ↑ Clinical trial number NCT02356302 for "Safety and Pharmacokinetics of Intravaginal Rings Containing Vicriviroc (MK-4176) and/or MK-2048" at ClinicalTrials.gov
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