Synthesis and SAR investigations for novel melanin-concentrating hormone 1 receptor (MCH1) antagonists part 2: A hybrid strategy combining key fragments of HTS hits.
A novel series of melanin-concentrating hormone (MCH1) receptor antagonists based on combining key fragments from the high-throughput screening (HTS) hits compound 2 (SNAP 7941) and compound 5 (chlorohaloperidol) are described. The resultant analogs, exemplified by compounds 11a-11h, 15a-15h, and 16a-16g, were evaluated in in vitro and in vivo assays for their potential in treatment of mood disorders. From further SAR investigations, N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide (16g, SNAP 94847) was identified to be a high affinity and selective ligand for the MCH1 receptor. Compound 16g also shows good oral bioavailability (59%) and exhibits a brain/plasma ratio of 2.3 in rats. Compound 16g showed in vivo inhibition of a centrally induced MCH-induced drinking effect and exhibited a dose-dependent anxiolytic effect in the rat social interaction model.
Chen
Chien-An
CA
Departments of Chemistry, Cellular Science and Target Discovery and Assessment, Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ 07652-1413, USA.
Jiang
Yu
Y
Lu
Kai
K
Daniewska
Irena
I
Mazza
Christine G
CG
Negron
Leonardo
L
Forray
Carlos
C
Parola
Tony
T
Li
Boshan
B
Hegde
Laxminarayan G
LG
Wolinsky
Toni D
TD
Craig
Douglas A
DA
Kong
Ron
R
Wetzel
John M
JM
Andersen
Kim
K
Marzabadi
Mohammad R
MR
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001007:Anxiety / Q000523:psychology; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004326:Drinking / Q000187:drug effects; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012919:Social Behavior
D014151:Anti-Anxiety Agents; C081782:Cap1 protein, rat; D003598:Cytoskeletal Proteins; D008024:Ligands; C519479:N-(3-(1-((4-(3,4-difluorophenoxy)phenyl)methyl)(4-piperidyl))-4-methylphenyl)-2-methylpropanamide; D010880:Piperidines; D011994:Recombinant Proteins; C040693:1-(3-(4-chlorobenzoyl)propyl)-4-hydroxy-4-(4-chlorophenyl)piperidine; D006220:Haloperidol