2. Academic Validation
  3. Synthesis and SAR investigations for novel melanin-concentrating hormone 1 receptor (MCH1) antagonists part 2: A hybrid strategy combining key fragments of HTS hits

Synthesis and SAR investigations for novel melanin-concentrating hormone 1 receptor (MCH1) antagonists part 2: A hybrid strategy combining key fragments of HTS hits

  • J Med Chem. 2007 Aug 9;50(16):3883-90. doi: 10.1021/jm060383x.
Chien-An Chen 1,  Yu Jiang,  Kai Lu,  Irena Daniewska,  Christine G Mazza,  Leonardo Negron,  Carlos Forray,  Tony Parola,  Boshan Li,  Laxminarayan G Hegde,  Toni D Wolinsky,  Douglas A Craig,  Ron Kong,  John M Wetzel,  Kim Andersen,  Mohammad R Marzabadi
Affiliations

Affiliation

  • 1 Departments of Chemistry, Cellular Science and Target Discovery and Assessment, Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ 07652-1413, USA.
PMID: 17668922 DOI: 10.1021/jm060383x
Abstract

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.

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