2. Academic Validation
  3. Constrained 7-fluorocarboxychromone-4-aminopiperidine based Melanin-concentrating hormone receptor 1 antagonists: the effects of chirality on substituted indan-1-ylamines

Constrained 7-fluorocarboxychromone-4-aminopiperidine based Melanin-concentrating hormone receptor 1 antagonists: the effects of chirality on substituted indan-1-ylamines

  • Bioorg Med Chem Lett. 2007 Feb 15;17(4):884-9. doi: 10.1016/j.bmcl.2006.11.061.
Andrew J Souers 1,  Rajesh R Iyengar,  Andrew S Judd,  David W A Beno,  Ju Gao,  Gang Zhao,  Michael E Brune,  James J Napier,  Mathew M Mulhern,  John K Lynch,  Jennifer C Freeman,  Dariusz Wodka,  Chong J Chen,  H Doug Falls,  Sevan Brodjian,  Brian D Dayton,  Gilbert J Diaz,  Eugene N Bush,  Robin Shapiro,  Brian A Droz,  Victoria Knourek-Segel,  Lisa E Hernandez,  Kennan C Marsh,  Regina M Reilly,  Hing L Sham,  Christine A Collins,  Philip R Kym
Affiliations

Affiliation

  • 1 Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. andrew.souers@abbott.com
PMID: 17188866 DOI: 10.1016/j.bmcl.2006.11.061
Abstract

The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.

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