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Details

Stereochemistry ABSOLUTE
Molecular Formula C21H21ClFN5O4
Molecular Weight 461.8747
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of MK-2048

SMILES

CCN1C[C@]([H])(C)n2c3c(c(c2C1=O)O)c(=O)n(Cc4ccc(c(c4)Cl)F)nc3C(=O)NC

InChI

InChIKey=JSRREMIKIHJGAA-JTQLQIEISA-N
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/h5-7,10,29H,4,8-9H2,1-3H3,(H,24,30)/t10-/m0/s1

HIDE SMILES / InChI

Molecular Formula C21H21ClFN5O4
Molecular Weight 461.8747
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment:: Description was created using several sources including: https://www.ncbi.nlm.nih.gov/pubmed/20799722|https://www.ncbi.nlm.nih.gov/pubmed/19906306

MK-2048, diketo acid derivative, is a second-generation integrase strand transfer inhibitor (INSTI) developed to retain activity against HIV containing mutations associated with resistance to first-generation INSTIs, raltegravir (RAL) and elvitegravir (EVG). MK-2048 implements its inhibitory mechanism by modifying viral integrase-DNA interactions, the important step of the linear HIV-1 cDNA integration into the host genome. It binds to and inactivates the synaptic complex, an intermediate in the concerted integration pathway in vitro thereby preventing target DNA binding and concerted integration. MK-2048 is active against viruses resistant to RAL and EVG. MK-2048 is equally potent against wild-type IN and raltegravir-resistant IN mutant N155H with a low IC50 value of 42 nM for inhibiting concerted integration. It inhibits R263K mutants slightly more effectively than G118R mutants. MK-2048 exposure leads to the selection of G118R as a possible novel resistance mutation.

Originator

Curator's Comment:: # Merck

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
0.08 µM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
728 pg/mL
30 mg 1 times / 4 weeks steady-state, vaginal
dose: 30 mg
route of administration: Vaginal
experiment type: STEADY-STATE
co-administered:
MK-2048 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
277172 pg × h/mL
30 mg 1 times / 4 weeks steady-state, vaginal
dose: 30 mg
route of administration: Vaginal
experiment type: STEADY-STATE
co-administered:
MK-2048 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
3 h
30 mg 1 times / 4 weeks steady-state, vaginal
dose: 30 mg
route of administration: Vaginal
experiment type: STEADY-STATE
co-administered:
MK-2048 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: UNKNOWN
PubMed

PubMed

TitleDatePubMed
Comparative biochemical analysis of HIV-1 subtype B and C integrase enzymes.
2009 Nov 11
Primary mutations selected in vitro with raltegravir confer large fold changes in susceptibility to first-generation integrase inhibitors, but minor fold changes to inhibitors with second-generation resistance profiles.
2010 Jul 5
Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor.
2010 Sep
Physical trapping of HIV-1 synaptic complex by different structural classes of integrase strand transfer inhibitors.
2010 Sep 28
Integrase inhibitors effective against human T-cell leukemia virus type 1.
2011 May
Comparative antiviral activity of integrase inhibitors in human monocyte-derived macrophages and lymphocytes.
2011 Nov
Patents

Sample Use Guides

Intravaginal rings MK-2048A IVR (Low Dose) (91 mg of vicriviroc, 10 mg of MK-2048) or MK-2048A IVR (Original Dose) (182 mg of vicriviroc, 30 mg of MK-2048) inserted during the enrollment visit, and removed on Day 28
Route of Administration: Vaginal
MK-2048 was investigated in primary human macrophages, PBMC and C8166-lymphocytic T cells, to determine its relative potency and efficacy in different cellular systems of HIV infection. MK-2048 showed anti HIV activity similar or slightly higher in macrophages compared to PBMC and C8166 T cells with the EC50 of 0.4, 0.9, 11.5 nM in macrophages, in PBMCs and T cells, respectively.
Substance Class Chemical
Created
by admin
on Sat Jun 26 10:09:55 UTC 2021
Edited
by admin
on Sat Jun 26 10:09:55 UTC 2021
Record UNII
LJ8U884TM5
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
MK-2048
Common Name English
PYRAZINO(1',2':1,5)PYRROLO(2,3-D)PYRIDAZINE-4-CARBOXAMIDE, 2-((3-CHLORO-4-FLUOROPHENYL)METHYL)-8-ETHYL-1,2,6,7,8,9-HEXAHYDRO-10-HYDROXY-N,6-DIMETHYL-1,9-DIOXO-, (6S)-
Systematic Name English
Code System Code Type Description
EPA CompTox
869901-69-9
Created by admin on Sat Jun 26 10:09:55 UTC 2021 , Edited by admin on Sat Jun 26 10:09:55 UTC 2021
PRIMARY
CAS
869901-69-9
Created by admin on Sat Jun 26 10:09:55 UTC 2021 , Edited by admin on Sat Jun 26 10:09:55 UTC 2021
PRIMARY
PUBCHEM
54698642
Created by admin on Sat Jun 26 10:09:55 UTC 2021 , Edited by admin on Sat Jun 26 10:09:55 UTC 2021
PRIMARY
FDA UNII
LJ8U884TM5
Created by admin on Sat Jun 26 10:09:55 UTC 2021 , Edited by admin on Sat Jun 26 10:09:55 UTC 2021
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
Mutations (G118R and E138K) confer resistance to MK-2048
TARGET ORGANISM->INHIBITOR
EC50
Related Record Type Details
ACTIVE MOIETY