title: De novo design of a picomolar nonbasic 5-HT(1B) receptor antagonist.
abstract: We describe herein the discovery of novel, de novo designed, 5-HT(1B) receptor antagonists that lack a basic moiety and that provide improved hERG and in vitro phospholipidosis profiles. We used a known 5-HT(1B) antagonist template as our starting point and focused on replacing the piperazine moiety. Pyrazole-based ideas were designed and synthesized among a small library of piperazine replacements. To our knowledge, these are the first potent, nonbasic, functionally active antagonists of the 5-HT(1B) receptor.
authors.affiliation: Department of CNS Chemistry, AstraZeneca Pharmaceuticals,1800 Concord Pike, Wilmington, Delaware 19850, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Nugiel
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Krumrine
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Hill
authors.forename: James R
authors.initials: JR
authors.lastname: Damewood
authors.forename: Peter R
authors.initials: PR
authors.lastname: Bernstein
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Sobotka-Briner
authors.forename: Jianwei
authors.initials: J
authors.lastname: Liu
authors.forename: Anna
authors.initials: A
authors.lastname: Zacco
authors.forename: M Edward
authors.initials: ME
authors.lastname: Pierson
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D054333:Drug Partial Agonism; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007035:Hypothermia / Q000188:drug therapy; D008064:Lipidoses / Q000139:chemically induced / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D010879:Piperazines / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology; D011720:Pyrazoles / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D013329:Structure-Activity Relationship
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010743:Phospholipids; D010879:Piperazines; D011720:Pyrazoles; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists