N-3-Substituted Imidazo Quinazolinones: Potent and Selective PDE5 Inhibitors As Potential Agents for Treatment of Erectile Dysfunction

Phosphodiesterase type 5 (PDE5) inhibitors with improved PDE isozyme selectivity relative to sildenafil may result in agents for the treatment of male erectile dysfunction (MED) with a lower incidence of PDE-associated adverse effects. This paper describes the discovery of 14, a PDE5 inhibitor with improved potency and selectivity in vitro compared to sildenafil. This compound shows activity in a functional assay of erectile function comparable to that of sildenafil

Optimization of Substituted N-3-Benzylimidazoquinazolinone Sulfonamides As Potent and Selective PDE5 Inhibitors

A previous report from these laboratories identified the N-3-benzylimidazoquinazolinone nucleus as a more selective PDE5 inhibitor template compared to the pyrazolopyrimidine of sildenafil. This paper describes in detail the structure-activity relationships of a set of sulfonamide analogues, several of which are both more potent and more selective PDE5 inhibitors in vitro than sildenafil. The synthesis, in vitro enzyme activity and selectivity, and in vitro functional and preclinical pharmacokinetic assessment of molecules in this series are described

Asymmetric Synthesis of Heterocyclic Analogues of a CGRP Receptor Antagonist for Treating Migraine

An asymmetric synthesis of novel heterocyclic analogue of the CGRP receptor antagonist rimegepant (BMS-927711, <b>3</b>) is reported. The cycloheptane ring was constructed by an intramolecular Heck reaction. The application of Hayashi–Miyaura and Ellman reactions furnished the aryl and the amine chiral centers, while the separable diastereomeric third chiral center alcohols led to both carbamate and urea analogues. This synthetic approach was applicable to both 6- and 5-membered heterocycles as exemplified by pyrazine and thiazole derivatives

The qEEG Signature of Selective NMDA NR2B Negative Allosteric Modulators; A Potential Translational Biomarker for Drug Development

<div><p>The antidepressant activity of the N-methyl-D-aspartate (NMDA) receptor channel blocker, ketamine, has led to the investigation of negative allosteric modulators (NAMs) selective for the NR2B receptor subtype. The clinical development of NR2B NAMs would benefit from a translational pharmacodynamic biomarker that demonstrates brain penetration and functional inhibition of NR2B receptors in preclinical species and humans. Quantitative electroencephalography (qEEG) is a translational measure that can be used to demonstrate pharmacodynamic effects across species. NMDA receptor channel blockers, such as ketamine and phencyclidine, increase the EEG gamma power band, which has been used as a pharmacodynamic biomarker in the development of NMDA receptor antagonists. However, detailed qEEG studies with ketamine or NR2B NAMs are lacking in nonhuman primates. The aim of the present study was to determine the effects on the qEEG power spectra of the NR2B NAMs traxoprodil (CP-101,606) and BMT-108908 in nonhuman primates, and to compare them to the NMDA receptor channel blockers, ketamine and lanicemine. Cynomolgus monkeys were surgically implanted with EEG radio-telemetry transmitters, and qEEG was measured after vehicle or drug administration. The relative power for a number of frequency bands was determined. Ketamine and lanicemine increased relative gamma power, whereas the NR2B NAMs traxoprodil and BMT-108908 had no effect. Robust decreases in beta power were elicited by ketamine, traxoprodil and BMT-108908; and these agents also produced decreases in alpha power and increases in delta power at the doses tested. These results suggest that measurement of power spectra in the beta and delta bands may represent a translational pharmacodynamic biomarker to demonstrate functional effects of NR2B NAMs. The results of these studies may help guide the selection of qEEG measures that can be incorporated into early clinical evaluation of NR2B NAMs in healthy humans.</p></div