title: Novel approach for chemotype hopping based on annotated databases of chemically feasible fragments and a prospective case study: new melanin concentrating hormone antagonists.
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.
authors.affiliation: Department of Molecular Informatics, Johnson & Johnson Pharmaceutical R&D, Toledo, Spain. joyarzabal@cnio.es
authors.forename: Julen
authors.initials: J
authors.lastname: Oyarzabal
authors.forename: Trevor
authors.initials: T
authors.lastname: Howe
authors.forename: Jesús
authors.initials: J
authors.lastname: Alcazar
authors.forename: Jose Ignacio
authors.initials: JI
authors.lastname: Andrés
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Alvarez
authors.forename: Frank
authors.initials: F
authors.lastname: Dautzenberg
authors.forename: Laura
authors.initials: L
authors.lastname: Iturrino
authors.forename: Sonia
authors.initials: S
authors.lastname: Martínez
authors.forename: Ilse
authors.initials: I
authors.lastname: Van der Linden
mesh_terms: D002491:Central Nervous System Agents / Q000737:chemistry; D016208:Databases, Factual; D055808:Drug Discovery; D007028:Hypothalamic Hormones / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008543:Melanins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis / Q000737:chemistry*; D010907:Pituitary Hormones / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D055672:Static Electricity; D013237:Stereoisomerism; D014867:Water / Q000737:chemistry
chemical_list: D002491:Central Nervous System Agents; D007028:Hypothalamic Hormones; D008543:Melanins; D004364:Pharmaceutical Preparations; D010907:Pituitary Hormones; D011719:Pyrazines; D011979:Receptors, Pituitary Hormone; D012997:Solvents; C092274:melanin-concentrating hormone receptor; D014867:Water; C019463:melanin-concentrating hormone