Design and Synthesis of Conformationally Constrained Analogs of 4-(3-Butoxy-4-methoxybenzyl)imidazolidin-2-one (Ro 20-1724) as Potent Inhibitors of cAMP-Specific Phosphodiesterase

Abstract

The synthesis and biological evaluation of cAMP-specific phosphodiesterase (PDE IV) inhibitors is described. The PDE IV inhibitor 4-(3-butoxy-4-methoxybenzyl)imidazolidin-2-one (Ro 20-1724, 2) was used as a template from which to design a set of rigid oxazolidinones, imidazolidinones, and pyrrolizidinones that mimic Ro 20-1724 but differ in the orientation of the carbonyl group. The endo isomer of each of these heterocycles was more potent than the exo isomer in an enzyme inhibition assay and a cellular assay, which measured TNF alpha secretion from activated human peripheral blood monocytes (HPBM). Imidazolidinone 4a inhibited human PDE IV with a Ki of 27 nM and TNF alpha secretion from HPBM with an IC50 of 290 nM. By comparison, Ro 20-1724 is significantly less active in these assays with activities of 1930 and 1800nM, respectively.

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

“…The clean condensation of 3 with monomethyl malonate with concomitant decarboxylation directly gave the known unsaturated ester 4 [22] in very high yield. Base-catalysed Michael addition of nitromethane to 4 proceeded smoothly to the known ester 5 [21], which was readily hydrolysed to the acid 6.…”

Synthesis of Substituted 5-(3-Hydroxypropyl)pyrrolidin-2-ones and Pyrrolizidinones from Nitroethane via C3 Functionalized 5,6-Dihydro-4H-1,2-oxazines: A Novel Approach to Some Analogues of the Antidepressant Rolipram

“…10 Thus, racemic pyrrolizidinone 4 ( Figure 1) is several times more active as a cAMP-specific phosphodiesterase (PDE IV) inhibitor than the known antidepressant Rolipram. 11 Scheme 2 shows the proposed three-step sequence for the transformation of cyclic oxime ethers 1 into pyrrolidinones 2 or pyrrolizidinones 3 (depending on the nature of the substituents at C6 of the oxazine ring). This method includes the selective reduction of a C=N bond (step 1), the subsequent hydrogenolysis of an N-O bond in intermediates 5, followed by pyrrolidinone ring closure (step 2) and, finally, removal of a CO 2 Me group, attached to the pyrrolidinone ring (step 3).…”

“…The previous synthesis of rac-4 from aldehyde 9 is also quite efficient (6 steps, 16.9% yield), 11 but it is not stereoselective and requires a chromatographic separation of diastereomers (c.a. 2:1 in favor of rac-4) in the last step of the synthesis.…”

Phosphodiesterase 4 inhibitors for the treatment of asthma

“…In the search for more potent analogues, oxazolidinones, imidazolidinones and pyrrolizidinone mimetics of Ro 20-1724 were synthesised by Glaxo [43,131,132]. Conformationally restricted endo analogues of the compounds were consistently more potent than the corresponding exo series with the most potent analogues being (19) (K i 27 ± 1 nM, inhibition of cAMP hydrolysis by recombinant PDE 4B; IC 50 290 nM for LPS-induced TNF-α secretion from human monocytes; Figure 4) [43].…”

“…Conformationally restricted endo analogues of the compounds were consistently more potent than the corresponding exo series with the most potent analogues being (19) (K i 27 ± 1 nM, inhibition of cAMP hydrolysis by recombinant PDE 4B; IC 50 290 nM for LPS-induced TNF-α secretion from human monocytes; Figure 4) [43]. In a another series of rolipram analogues, the structure-activity relationship (inhibition of PDE 4B-mediated cAMP hydrolysis) was analysed for a number of 1-carbamate-, urea-or amide-substituted pyrrolidines.…”