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Details

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
Structure of MRK-409

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

HIDE SMILES / InChI

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

Description

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

Targets

Primary TargetPharmacologyConditionPotency
0.21 nM [Ki]
0.22 nM [Ki]
0.23 nM [Ki]
0.4 nM [Ki]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

PubMed

Sample Use Guides

In Vivo Use Guide
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
In Vitro Use Guide
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.
Substance Class Chemical
Record UNII
9VSE02330I
Record Status Validated (UNII)
Record Version