De novo design of a picomolar nonbasic 5-HT(1B) receptor antagonist.
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.
Nugiel
David A
DA
Department of CNS Chemistry, AstraZeneca Pharmaceuticals,1800 Concord Pike, Wilmington, Delaware 19850, USA.
Krumrine
Jennifer R
JR
Hill
Daniel C
DC
Damewood
James R
JR
Bernstein
Peter R
PR
Sobotka-Briner
Cynthia D
CD
Liu
Jianwei
J
Zacco
Anna
A
Pierson
M Edward
ME
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
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