Novel approach for chemotype hopping based on annotated databases of chemically feasible fragments and a prospective case study: new melanin concentrating hormone antagonists

  • J Med Chem. 2009 Apr 9;52(7):2076-89. doi: 10.1021/jm8016199.
Julen Oyarzabal  1 ,  Trevor Howe ,  Jesús Alcazar ,  Jose Ignacio Andrés ,  Rosa M Alvarez ,  Frank Dautzenberg ,  Laura Iturrino ,  Sonia Martínez ,  Ilse Van der Linden
Affiliations
  • 1. Department of Molecular Informatics, Johnson & Johnson Pharmaceutical R&D, Toledo, Spain. [email protected]
PMID: 19290642 DOI: 10.1021/jm8016199
Abstract

A novel strategy for chemotype hopping, based on annotated databases of chemically feasible fragments and their oriented functionalization, is presented. A three-dimensional (3D) similarity analysis of project-oriented functionalized scaffolds provides a prioritized proposal for synthesis with the most appropriate linkers and optimal regiochemistry on R-groups. This strategy maximizes the potential of proprietary and commercially available compounds. A retrospective and prospective case study, on melanin concentrating hormone (MCH) antagonists, showing the impact on the drug discovery process of this new strategy by maintaining primary activity and improving key ADME/Tox property while enhancing intellectual property (IP) position is demonstrated.