Novel approach for chemotype hopping based on annotated databases of chemically feasible fragments and a prospective case study: new melanin concentrating hormone antagonists.
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.
Oyarzabal
Julen
J
Department of Molecular Informatics, Johnson & Johnson Pharmaceutical R&D, Toledo, Spain. joyarzabal@cnio.es
Howe
Trevor
T
Alcazar
Jesús
J
Andrés
Jose Ignacio
JI
Alvarez
Rosa M
RM
Dautzenberg
Frank
F
Iturrino
Laura
L
Martínez
Sonia
S
Van der Linden
Ilse
I
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
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