Phosphodiesterase Type IV Inhibition. Structure-Activity Relationships of 1,3-Disubstituted Pyrrolidines

Abstract

The synthesis of 1,3-disubstituted pyrrolidines 2 and their activities as type IV phosphodiesterase (PDE) inhibitors are described. Various groups were appended to the nitrogen of the pyrrolidine nucleus to enable structure-activity relationships to be assessed. Groups which render the pyrrolidine nitrogen of 2 nonbasic yielded potent PDE-IV inhibitors. Analogs of amides, carbamates, and ureas of 2 were synthesized to determine the effects that substitution on these functional groups had on PDE-IV inhibitor potency. The structural requirements for PDE-IV inhibitor potency differed among the three classes. A representative amide, carbamate, and urea (2c,d,h) were shown to be > 50-fold selective for inhibiting PDE-IV versus representative PDEs from families I-III and V. Furthermore, these same three inhibitors demonstrated potent functional activity (IC50 < 1 microM) by inhibiting tumor necrosis factor-alpha (TNF-alpha) release from lipopolysaccharide (LPS)-activated purified human peripheral blood monocytes and mouse peritoneal macrophages. These compounds were also tested orally in LPS-injected mice and demonstrated dose-dependent inhibition of serum TNF-alpha levels.

Novel Selective PDE IV Inhibitors as Antiasthmatic Agents. Synthesis and Biological Activities of a Series of 1-Aryl-2,3-bis(hydroxymethyl)naphthalene Lignans

“…An area of recent interest has been the search for selective PDE IV inhibitors as potential antiasthmatic agents . The reported selective PDE IV inhibitors include catechol ethers, quinazolinediones, and xanthines. 4c, During our continued search for biologically active lignans, we found that arylnaphthalene lignans showed consistent PDE IV inhibitory activity as a class. Since inhibition of PDE III is reported to correlate with the induction of cardiovascular side effects, we undertook a search for PDE IV inhibitors having minimal PDE III inhibitory activity in the lignan series.…”

Phosphodiesterase 4 inhibitors for the treatment of asthma

“…The potency of the carbamates generally increased with increasing lipophilicity, although this was not true for the amides and ureas. About a 10-fold improvement in K i over rolipram was achieved in this series of compounds, but it is unclear how well this translated into improved activity in vivo [44]. Several different series of rolipram analogues, featuring substitution in the cyclopentyl ring for exo-norbornyl group and substitution of the pyrrolidinone ring for 3,4,5,6-tetrahydropyrimidin-2-(1H)-one have been been published by Pfizer [133][134][135][136][137][138][139][140][141].…”

N-[(1R)-1-(4-Chlorophenyl)ethyl]-Cyanamide

“…Cyanamides are attractive 1C-2N building blocks for the construction of nitrogenrich molecules such as amidines, guanidines, or ureas [1][2][3]. Moreover, the cyanamide moiety is present in a number of biologically active molecules, such as the cathepsin K protease and the type 4 phosphodiesterase inhibitors A [4] and B [5], respectively, or the insecticides thiacloprid (C) [6] and sulfoxaflor (D) [7] (see Figure 1). According to their significance in synthetic organic chemistry, a large variety of methods for the preparation of cyanamides have been developed [1][2][3]8].…”