MK-2048 explained

Iupac Name:(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
Legal Us:Investigational New Drug
Cas Number:869901-69-9
Unii:LJ8U884TM5
Atc Prefix:none
Pubchem:11554427
Chembl:1237018
Chemspiderid:25058456
C:21
H:21
Cl:1
F:1
N:5
O:4
Stdinchi: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
Stdinchikey:IOYLKNABOQYKKY-JTQLQIEISA-N
Smiles:CCN1CC(N2C3=C(C(=O)C2=C1O)C(=O)N(N=C3C(=O)NC)CC4=CC(=C(C=C4)F)Cl)C

MK-2048 is the Merck & Co. designation for a molecule in its pre-clinical drug discovery portfolio that is an integrase inhibitor-class of agent selected for development as a preventative treatment against HIV infection.[1] Its second generation integrase design was hypothesized to be superior to the first available integrase inhibitor, raltegravir, in that "MK-2048 has a dissociation half-life of 32 hours on wild-type integrase—more than four times that of raltegravir",[1] [2] and its dissociation half-life against the important HIV integrase mutant N155H was on the same order of magnitude as that of raltegravir against wild-type virus. These findings led Merck representatives to suggest the possibility of "reduced susceptibility to resistance mutations" for the second generation drug.[1] MK-2048 has been investigated for use as part of a pre-exposure prophylaxis (PrEP) approach to the treatment of HIV infection;[3] however, the results of a 2015-2016 placebo-controlled human clinical trial indicated no observed correlation between tissue-associated VCV and/or MK-2048 and the inhibition of HIV infection, limiting expectations for this compound's efficacy for such applications.[4] At the time of these reports, there was no indication of the time by which "MK-2048, or related compounds, [would] be ready for clinical trials".[1]

Notes and References

  1. Mascolini M . Conference Reports for NATAP: Merck Offers Unique Perspective on Second-Generation Integrase Inhibitor . 10th International Workshop on Clinical Pharmacology of HIV Therapy . April 2009 . Amsterdam] . NATAP.org . November 8, 2009 . June 4, 2017 . https://web.archive.org/web/20170604023850/http://www.natap.org/2009/PK/PK_10.htm . live .
  2. Grobler JA, McKenna PM, Ly S, Stillmock K, Bahnck C, Danovich RM, Dornadula G, Hazuda DJ, Miller MD . 6 . Presentation, Abstract O-10: Functionally Irreversible Inhibition of Integration by Slowly Dissociating Strand Transfer Inhibitors. . 10th International Workshop on Clinical Pharmacology of HIV Therapy . April 2009 . Amsterdam] . NATAP.org .
  3. Web site: Alcorn K . April 28, 2009 . Ralvetgravir Shows Potential for use as PrEP Drug . AIDSmap.com . November 8, 2009 . https://web.archive.org/web/20100103034130/http://www.aidsmap.com/en/news/B30D4C80-B2C3-4912-84E7-3EF4F414360A.asp . January 3, 2010 . dead .
  4. Hoesley CJ, Chen BA, Anderson PL, Dezzutti CS, Strizki J, Sprinkle C, Heard F, Bauermeister J, Hall W, Jacobson C, Berthiaume J, Mayo A, Gundacker H, Richardson-Harman N, Piper J . 6 . Phase 1 Safety and Pharmacokinetics Study of MK-2048/Vicriviroc (MK-4176)/MK-2048A Intravaginal Rings . Clinical Infectious Diseases . 68 . 7 . 1136–1143 . March 2019 . 30289435 . 6424075 . 10.1093/cid/ciy653 .