Crystal structure, absolute configuration, and phosphodiesterase inhibitory activity of (+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidinone

Abstract

Chiral HPLC resolution of the phosphodiesterase IV (PDE IV) inhibitor rolipram (1) provided (-)-1, and this enantiomer was converted into its 1-(4-bromobenzyl) derivative, (+)-2. X-ray structural analysis of (+)-2 established the absolute configuration as R, which provides the first direct evidence for a previously assumed assignment of configuration. The crystal structure of (+)-2 and the PDE inhibitory activity of both enantiomers of 2 are discussed in the context of a previously proposed topological model.

Inhibitor Binding to Type 4 Phosphodiesterase (PDE4) Assessed Using [3H]Piclamilast and [3H]Rolipram

“…Interestingly, the rank-order potency of a variety of compounds for inhibiting PDE4 catalytic activity differs from their rank-order potency for competing with [ 3 H]rolipram binding to the HARBS (Torphy et al, 1992;Baures et al, 1993). Although the function of the HARBS is unknown, the potency of PDE4 inhibitors to produce certain effects, such as emesis and increased gastric acid secretion, correlates with their ability to displace [ 3 H]rolipram from this site.…”

Enantiodivergent Synthesis of (R)- and (S)-Rolipram

“…The industrial synthesis of rac- (1) and resolution of the enantiomers either chromatographically [13][14][15] or by classical (enzymatic) resolution of an intermediate in the synthesis [16] has been reported. Asymmetric syntheses of 1 have been recently reviewed [17].…”

A Pharmacophore Model for PDE IV Inhibitors

“…Three different hydrogen donor binding sites A, B and C can be defined. Crystal structure [ 161 5-phenylpentyl substituent significantly reduces the emetic side effects [lo].…”