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.

David A. Nugiel, Jennifer R. Krumrine, Daniel C. Hill, James R. Damewood Jr, Peter R. Bernstein, Cynthia D. Sobotka-Briner, JianWei Liu, Anna Zacco, M. Edward Pierson
February 25, 2010
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