Synthesis and SAR investigations for novel melanin-concentrating hormone 1 receptor (MCH1) antagonists Part 1. The discovery of arylacetamides as viable replacements for the dihydropyrimidinone moiety of an HTS hit.
Melanin-concentrating hormone (MCH) is involved in the regulation of feeding, water balance, energy metabolism, general arousal and attention state, memory, cognitive functions, and psychiatric disorders. Herein, two new chemical series exemplified by N-[5-(1-{3-[2,2-bis-(4-fluoro-phenyl)-acetylamino]-propyl}-piperidin-4-yl)-2,4-difluoro-phenyl]-isobutyramide (SNAP 102739, 5m) and N-[3-(1-{3-[(S)-2-(4-fluoro-phenyl)-propionylamino]-propyl}-piperidin-4-yl)-4-methylphenyl]-isobutyramide ((S)-6b) are reported. These compounds were designed to improve the pharmacokinetic properties of the high-throughput screening lead compound 1 (SNAP 7941). The MCH1 receptor antagonists 5m and (S)-6b show reasonable pharmacokinetic profiles (rat bioavailability = 48 and 81%, respectively). Compounds 5m and (S)-6b demonstrated the inhibition of a centrally administered MCH-evoked drinking effect, and compound 5m exhibited oral in vivo efficacy in the rat social interaction model of anxiety, with a minimum effective dose = 0.3 mg/kg.
Jiang
Yu
Y
Departments of Chemistry, Cellular Science, and Target Discovery and Assessment, Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ 07652-1413, USA.
Chen
Chien-An
CA
Lu
Kai
K
Daniewska
Irena
I
De Leon
John
J
Kong
Ron
R
Forray
Carlos
C
Li
Boshan
B
Hegde
Laxminarayan G
LG
Wolinsky
Toni D
TD
Craig
Douglas A
DA
Wetzel
John M
JM
Andersen
Kim
K
Marzabadi
Mohammad R
MR
D000081:Acetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000813:Anilides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001007:Anxiety / Q000523:psychology; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004326:Drinking / Q000187:drug effects; D006801:Humans; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012919:Social Behavior; D013237:Stereoisomerism
D000081:Acetamides; D000813:Anilides; D014151:Anti-Anxiety Agents; C081782:Cap1 protein, rat; D003598:Cytoskeletal Proteins; C524110:N-(3-(1-(3-(2-(4-fluorophenyl)propionylamino)propyl)piperidin-4-yl)-4-methylphenyl)isobutyramide; C524109:N-(5-(1-(3-(2,2-bis(4-fluorophenyl)acetylamino)propyl)piperidin-4-yl)-2,4-difluorophenyl)isobutyramide; D010880:Piperidines; D011743:Pyrimidines; D011994:Recombinant Proteins; D002118:Calcium