Characterization of Pyrrolidinyl-hexahydro-pyranopiperazines as a Novel Kappa Opioid Receptor Agonist Scaffold

The kappa agonist structure–activity relationship around the novel, pyrrolidinyl substituted pyranopiperazine scaffold was developed. More specifically, the dichloroPhenylAcetamide-Pyrrolidinyl-PyranoPiperazine (PAPPP) core A was the focus of our work. The modulation of kappa receptor potency/G-protein activation and arrestin recruitment with respect to changes of the piperazine R group in A was demonstrated. Reduced β2-arrestin recruitment and differential G-protein bias were observed for select analogues. To better understand the subtlety in receptor signaling, analogues were profiled as the resolved enantiomers. To determine in vivo target engagement, a subset of compounds was tested in mice for stimulation of serum prolactin, a neuroendocrine biomarker of KOR-agonist effects. Additional in vivo characterization included measurement of potential unwanted effects of kappa receptor activation such as sedation. These studies demonstrate a novel kappa receptor agonist scaffold with potential for G-protein signaling bias to probe in vivo pharmacology

Transformation of Peptides into Non-Peptides. Synthesis of Computer-Generated Enzyme Inhibitors: Computer-Assisted Drug Design

With the intent of discovering novel molecular scaffolds for designing protease inhibitors, the computer program GrowMol was used to generate peptidemimetic inhibitors of aspartic proteases. Beginning with the X-ray crystal structure of A66702 complexed to pepsin, GrowMol successfully generated a series of known cyclic inhibitors of pepsin in which the cysteine side chains in the P1 and P3 inhibitor subsites are connected. GrowMol also created a series of novel urea-derived inhibitors of pepsin, a series of α,α-disubstituted amino-alcohol-derived structures, and a series of cyclohexanol-derived inhibitors in which the core portion of the inhibitor lacks nitrogen. The paper describes the iterative process of selection and synthesis of computer-generated structure, determination of activity, and reassessment of potency with respect to the beginning crystal structure. These efforts led to the synthesis of analogs 9–12 which are novel pepsin inhibitors with moderate inhibitory activity. Attempts to crystallize these inhibitors in the active site of pepsin to determine if compounds 9–12 bind as predicted by GrowMol are in progress