(3-Phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines: potent and selective antagonists of the serotonin 5-HT6 receptor.

Abstract

5-HT(6) receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT(6) receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT(6) receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT(2B) receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data.

• Authors: Alexandre V Ivachtchenko, Dmitri E Dmitriev, Elena S Golovina, Madina G Kadieva, Angela G Koryakova, Volodymyr M Kysil, Oleg D Mitkin, Ilya M Okun, Sergey E Tkachenko, Anton A Vorobiev
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 14 Pg. 5186-96 (Jul 22 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20560595 (Publication Type: Journal Article)

Chemical References

• Amines
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• KCNH2 protein, human
• N-methyl-(3-phenylsulfonyl)-7,8-dihydro-6H-cyclopenta(e)pyrazolo(1,5-a)pyrimidin-2-amine
• Pyrazoles
• Pyrimidines
• Receptors, Serotonin
• Serotonin 5-HT2 Receptor Antagonists
• Serotonin Antagonists
• Sulfones
• serotonin 6 receptor

Topics

• Amines (chemical synthesis, chemistry, pharmacology)
• Cell Line
• Crystallography, X-Ray
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels (antagonists & inhibitors)
• Humans
• Models, Molecular
• Molecular Structure
• Pyrazoles (chemical synthesis, chemistry, pharmacology)
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Radioligand Assay
• Receptors, Serotonin (metabolism)
• Serotonin 5-HT2 Receptor Antagonists
• Serotonin Antagonists (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Sulfones (chemical synthesis, chemistry, pharmacology)