Cathy Dantzman

The discovery of non-basic atrial natriuretic peptide clearance receptor antagonists. Part 1

The cyclic peptide ANP 4-23 and the linear peptide analogue AP-811 have been shown to be selective ANP-CR antagonists. Via alanine scanning and truncation studies we sought to determine which residues in these molecules were important in their binding to the clearance receptor and the relationship between these two molecules. These studies show that several modifications to these compounds are possible which improve physical properties of these molecules while retaining high affinity for the ANP-CR.

4-Piperidin-4-ylidenemethyl-benzamides as δ-opioid receptor agonists for CNS indications: identifying clinical candidates.

A series of 4-piperidin-4-ylidenemethyl-benzamide δ-opioid receptor agonists is described with an emphasis on balancing the potency, subtype selectivity and in vitro ADME and safety properties. The three sites impacting SAR are substitutions on the aryl group (R(1)), the piperidine nitrogen (R(2)), and the amide (R(3)). Each region contributes to the balance of properties for δ opioid activity and a desirable CNS profile, and two clinical candidates (20 and 24) were advanced.

Multiparameter exploration of piperazine derivatives as δ-opioid receptor agonists for CNS indications

A novel series of piperazine derivatives exhibits sub-nanomolar binding and enhanced subtype selectivity as δ-opioid agonists. The synthesis and SAR are described as well as the application of computational models to improve in vitro ADME and safety properties suitable for CNS indications, specifically microsomal clearance, permeability, and hERG channel inhibition.

The discovery of orally-active pseudopeptide antagonists of the atrial natriuretic peptide clearance receptor

Robert T. Jacobs, David Aharony, Vernon Alford, Russell A. Bialecki, Steven E. Cook, Cathy L. Dantzman, Timothy W. Davenport, Steven T. Dock, Philip D. Edwards, Greg A. Hostetler, Alan Kirschner, Russell C. Mauger, Megan Murphy, William E. Palmer, Kara K. Pine, William L. Rumsey, Gary B. Steelman, Jean M. Surian, Mark Sylvester, Edward P. Vacek, and Chris A. Veale AstraZeneca, a Business Unit of Zeneca Inc., Wilmington, DE 19897, U.S.A.