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

Yu Jiang; Chien-An Chen; Kai Lu; Irena Daniewska; John De Leon; Ron Kong; Carlos Forray; Boshan Li; Laxminarayan G Hegde; Toni D Wolinsky; Douglas A Craig; John M Wetzel; Kim Andersen; Mohammad R Marzabadi

doi:10.1021/jm060381c

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

J Med Chem. 2007 Aug 9;50(16):3870-82. doi: 10.1021/jm060381c.

Authors

Yu Jiang¹, Chien-An Chen, Kai Lu, Irena Daniewska, John De Leon, Ron Kong, Carlos Forray, Boshan Li, Laxminarayan G Hegde, Toni D Wolinsky, Douglas A Craig, John M Wetzel, Kim Andersen, Mohammad R Marzabadi

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: 17668921
DOI: 10.1021/jm060381c

Abstract

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.

MeSH terms

Acetamides / chemical synthesis*
Acetamides / pharmacokinetics
Acetamides / pharmacology
Anilides / chemical synthesis*
Anilides / pharmacokinetics
Anilides / pharmacology
Animals
Anti-Anxiety Agents / chemical synthesis*
Anti-Anxiety Agents / pharmacokinetics
Anti-Anxiety Agents / pharmacology
Anxiety / psychology
Biological Availability
Brain / metabolism
Calcium / metabolism
Cell Line
Cytoskeletal Proteins / antagonists & inhibitors*
Cytoskeletal Proteins / metabolism
Drinking / drug effects
Humans
Male
Piperidines / chemical synthesis*
Piperidines / pharmacokinetics
Piperidines / pharmacology
Pyrimidines / chemistry*
Radioligand Assay
Rats
Rats, Sprague-Dawley
Recombinant Proteins / antagonists & inhibitors
Recombinant Proteins / metabolism
Social Behavior
Stereoisomerism

Substances

Acetamides
Anilides
Anti-Anxiety Agents
Cap1 protein, rat
Cytoskeletal Proteins
N-(3-(1-(3-(2-(4-fluorophenyl)propionylamino)propyl)piperidin-4-yl)-4-methylphenyl)isobutyramide
N-(5-(1-(3-(2,2-bis(4-fluorophenyl)acetylamino)propyl)piperidin-4-yl)-2,4-difluorophenyl)isobutyramide
Piperidines
Pyrimidines
Recombinant Proteins
Calcium