| Stereochemistry | ACHIRAL |
| Molecular Formula | C19H17F2N7O |
| Molecular Weight | 397.3814 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CN1N=CN=C1COC2=NN3C(C=C2C4CCC4)=NN=C3C5=C(F)C=CC=C5F
InChI
InChIKey=GOIFCXRIFSYPFG-UHFFFAOYSA-N
InChI=1S/C19H17F2N7O/c1-27-16(22-10-23-27)9-29-19-12(11-4-2-5-11)8-15-24-25-18(28(15)26-19)17-13(20)6-3-7-14(17)21/h3,6-8,10-11H,2,4-5,9H2,1H3
| Molecular Formula | C19H17F2N7O |
| Molecular Weight | 397.3814 |
| Charge | 0 |
| Count |
MOL RATIO
1 MOL RATIO (average) |
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
MRK-409 (MK-0343) is a subtype-selective GABA(A) partial agonist that occupies the benzodiazepine site of GABA(A) receptors. MK-0343 was designed to be a less sedating anxiolytic, based on reduced efficacy at the alpha-1 subtype and significant efficacy at alpha -2 and alpha-3 subtypes of the GABA(A) receptor. MRK-409 binds to alpha-1, 2, 3 and 5-containing human recombinant GABA(A) receptors with comparable high affinity (0.21-0.40 nM). However, MRK-409 has greater agonist efficacy at the alpha-3 compared with alpha-1 subtypes. MRK-409 exhibited anxiolytic and non-sedating properties in different rodent and primate models of unconditioned and conditioned models of anxiety but produced sedation in man at relatively low levels of GABA(A) receptor occupancy (∼10%). It was suggested that the sedation with MRK-409 was due to the partial agonist efficacy of that compound at the alpha-1 subtype. Although MRK-409 (MK-0343) reached clinical studies its development had to be stopped due to sedative effects in humans demonstrated that more preclinical efforts are needed to identify compounds with improved selectivity.
CNS Activity
Originator
Approval Year
PubMed
Patents
Sample Use Guides
A single oral dose MK-0343 (MRK-409 ) 0.25 mg or 0.75 mg was administered with 250 mL of water in a fasted state at approximately 9–10 am on each treatment day in placebo controlled, randomized, double-blind, double-dummy, four-way, cross-over, single-center study in 12 healthy male volunteers, with at least a 5-day washout period.
Route of Administration:
Oral
MRK-409 Ki values mesured in mouse fibroblast L(tk) cells expressing human recombinant GABA(A) receptors were ranging from 0.21 to 0.40 nM for subtypes alpha-1, 2, 3 and 5 containing GABA(A) receptors and for the alpha-4 and 6 subtypes 78 and 980 nM, respectively. The affinities measured in native rat cerebellum and spinal cord receptors were 0.28 and 0.27 nM, respectively.
