De novo design of a picomolar nonbasic 5-HT(1B) receptor antagonist

  • J Med Chem. 2010 Feb 25;53(4):1876-80. doi: 10.1021/jm901200t.
David A Nugiel  1 ,  Jennifer R Krumrine ,  Daniel C Hill ,  James R Damewood Jr ,  Peter R Bernstein ,  Cynthia D Sobotka-Briner ,  Jianwei Liu ,  Anna Zacco ,  M Edward Pierson
Affiliations
  • 1. Department of CNS Chemistry, AstraZeneca Pharmaceuticals,1800 Concord Pike, Wilmington, Delaware 19850, USA.
PMID: 20088516 DOI: 10.1021/jm901200t
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.

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