MK-8262

Protein target name:

CETP

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

up to 5 uM

Probe Information

Target and Probe Information

Target Details

Target class:

Lipid metabolism

Subclass:

Lipid transfer protein

HUGO ID:

HGNC:1869

Entrez gene ID:

1071

UNIPROT ID:

P11597

Target alias:

BPIFF, HDLCQ10

Probe Details

Chemical Probes Portal ID:

CPP2468

Probe alias:

cpd 87

PubChem CID:

156596427

SMILES string:

O=C1OC(C2=CC(C(F)(F)F)=CC(C(F)(F)F)=C2)[C@@]3(CC[C@H](N13)C4=CC(C(F)(F)F)=CC=C4C5=CC(C6=CC=C(C(O)=O)C=C6C)=CN=C5OC)[H]

InChi Key:

VYZPBLVSILOWMJ-ASYYUYISSA-N

Physico-chemical properties

NMR:

1H NMR (CDCl3, 400 MHz) δ 8.29 (t, J = 2.6 Hz, 1H), 8.06 (m, 2H), 7.90 (s, 1H), 7.63-7.84 (m, 3H), 7.38-7.47 (m, 4H), 6.06-6.11 (m, 3H), 4.96-5.27 (tt, J = 8.2 Hz, J = 8.2 Hz, 1H), 4.51-4.66 (m, 1H), 3.94-4.11 (s, 3H), 2.32-2.49 (m, 3.5H), 1.86- 2.03 (m, 1H), 1.54 (m, 1H), 1.40 (m, 0.5H), 1.10 (m, 1H);

13C NMR (CDCl3, 100 MHz) δ 171.4, 171.3, 160.3, 160.1, 146.8, 146.7, 142.7, 142.6, 139.9, 138.3, 136.2, 132.5, 132.3, 132.2, 131.2, 130.2, 127.9, 125.3, 124.3, 122.4, 121.6, 118.8, 75.3, 75.1, 64.6, 64.2, 60.9, 60.6, 54.2, 53.7, 35.6, 35.4, 28.5, 20.5

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50Ki

20-53 nM (5-95 % plasma),120 nM (Ki)

Potency assay:

In vitro radioactive assays (RTA assay), Competition binding assays against 3H-torcetrapib (Ki)

Structure-activity relationship:

yes

Off target activity

Probe Selectivity in Vitro:

PanLabs and Cerep confirmed MK-8262 has inhibitory activity at the human Cox-2 enzyme, with an IC50 of 4 uM, and is an inhibitor of rat androgen receptor binding with an IC50 of 0.58 uM and also of functional activity with an IC50 of 2 uM.

Chem Partner using human androgen receptor binding and functional assays indicated that MK-8262 inhibits human androgen receptor binding with an IC50 of 0.92 uM and functional activity with an IC50 of 3.53 uM

In cell validation

On target activity in cells

Potency assay (cells):

In vitro radioactive assays (RTA assay)

Toxicity

Cytoxicity assay:

Yes

Notes on cytotoxicity:

Reduced cell viability beginning at ~10 uM

In vivo validation

Organism:

CD1 Mice, WH Rats, Beagle Dogs, Rhesus Monkeys

Dose:

2 mg/Kg PO, 0.5-1 mg/Kg IV

Route of delivery:

OralIntravenous

Plasma half life:

4.4 (M), 8.1 (R), 15 (D), 50 (m) h (terminal)6.0 (M), 13 (R), 18 (D), 60 (m) h (MRT)

Systemic clearance:

2.6 (M), 3.1 (R), 0.52 (D), 0.39 (m) ml/min/Kg

Cmax:

0.43 (M), 0.4 (R), 0.69 (D), 0.22 (m) uM

Tmax:

2.7 (M), 4.0 (R), 1.7 (D), 6.7 (m) h

Vss:

0.95 (M), 2.4 (R), 0.54 (D), 1.3 (m) L/kg

AUC:

7.9 (M), 9.7 (R), 13 (D), 11 (m) μM·h (0–∞)

Bioavailability:

43 (M), 65 (R), 14 (D), 8.4 (m) %

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.1c00959

Reference (PMID):

34375108

MK-8262

Probe Information

Target Details

BPIFF, HDLCQ10

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?

Search form

MK-8262

Probe Information

Target Details

BPIFF, HDLCQ10

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?