A Pharmacophore Model for PDE IV Inhibitors

Polymeropoulos, Emmanuel E.; Höfgen, Norbert

doi:10.1002/qsar.19970160307

Cited by 12 publications

(4 citation statements)

References 11 publications

(6 reference statements)

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“…Inhibitors of type IV phosphodiesterase (PDE) are considered as perspective anti-inflammatory and antidepressant drugs, among which are well-known rolipram (IC 50 = 175 nM), Ro 20-1724 , (IC 50 = 1590 nM) and cilomilast ,, (IC 50 = 92 nM). 7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3 H -pyrrolizin-3-one 1 (Scheme ) introduced by GlaxoSmithKline is a highly selective PDE IV inhibitor (IC 50 = 63 nM) several times more potent than rolipram .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of PDE IVb Inhibitors. 1. Asymmetric Synthesis and Stereochemical Assignment of (+)- and (−)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one

et al. 2011

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Asymmetric synthesis of GlaxoSmithKline's highly potent phosphodiesterase inhibitor 1 has been accomplished in nine steps and 16% overall yield. The original strategy suggested involves as a key step the silylation of enantiopure six-membered cyclic nitronates 4 obtained by a highly stereoselective [4 + 2]-cycloaddition of an appropriate nitroalkene 5 to trans-1-phenyl-2-(vinyloxy)cyclohexane. Functionalization of the resulting 5,6-dihydro-4H-1,2-oxazine and subsequent stereoselective reduction of 1,2-oxazine ring in intermediate 2 furnished the pyrrolizidinone framework with the recovery of chiral auxiliary alcohol.

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Section: Introductionmentioning

confidence: 99%

Synthesis of PDE IVb Inhibitors. 1. Asymmetric Synthesis and Stereochemical Assignment of (+)- and (−)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one

et al. 2011

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“…In this model, AL is a hydrogen bond acceptor atom, such as an ether or a carbonyl oxygen, HY is a hydrophobic center, such as the center of a phenyl or heterocyclic ring, DS are two hydrogen bond donor sites hypothesized as being present in the biological counterpart, in correspondence to AL sites on the ligand. The four pharmacophoric points de®ned by Model A do not give any new information regarding the knowledge of PDE4 catalytic site, however they con®rm those features described by previous models such as a relatively¯at topography (Marivet et al) [3] and a hydrogen bond acceptor atom adjacent to a lipophilic pocket (Polymeropoulos et al) [4,6]. Furthermore, it is interesting to note how these features partially match those displayed by low selective PDE3 inhibitors [31].…”

Section: Resultsmentioning

confidence: 70%

An Updated Topographical Model for Phosphodiesterase 4 (PDE4) Catalytic Site

Fossa

Menozzi

Mosti

2001

Quant. Struct.-Act. Relat.

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Preclinical and clinical studies on cyclic nucleotide phosphodiesterases 4 (PDE4) inhibitors showed that these agents might be employed in the treatment of allergic diseases, in particular asthma. Unfortunately, many of these compounds such as rolipram, which belongs to the so-called`® rst generation'', showed undesirable side effects such as nausea and emesis. Efforts to eliminate these adverse side effects prompted the synthesis of a``second generation'' of PDE4 inhibitors, with improved selectivity towards the enzyme catalytic site. So as to re®ne the pharmacophoric models of the catalytic site previously described in literature and better de®ne the structural requirements which are essential for potent and selective PDE4 inhibition, we undertook the present computational study. DISCO approach was applied to generate an optimal alignment for a set of structurally diverse selective inhibitors 1±18 chosen from literature. The resulting superimposition of common pharmacophoric elements was re®ned by evaluating molecular ®eld properties. A rational pharmacophoric model of the enzyme active site was thus derived and tested for its ability in predicting the degree of potency for a novel ligand. The comparison of the pharmacophoric areas common to cAMP, the natural substrate of the enzyme, and the most selective inhibitors was performed so as to better understand the binding mode of PDE4 selective inhibitors in the catalytic site.

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“…The structures were aligned to a ®rst approximation by calculating GRID-contours [9] for hydrogen donor sites as described in ref. 3. PrGen generates vectors (H-extension, lone-pair, hydrophobicity) for all functional groups.…”

Section: Methodsmentioning

confidence: 99%

“…Structural variation of PDE 4 inhibitors has been limited mainly to three types of compounds: rolipram and nitraquazone analogues and xanthine derivatives. The structural requirements for inhibiting catalytic activity have been recently analyzed by calculating GRID-contours for hydrogen donor binding sites [3]. The resulting pharmacophore hypothesis is schematically shown in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

A Peptidic Binding Site Model for PDE 4 Inhibitors

Polymeropoulos¹,

Höfgen²

1999

Quant. Struct.-Act. Relat.

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The pseudoreceptor modelling program PrGen was used to construct a peptidic binding site model for phosphodiesterase 4 inhibitors. A training set of 21 diverse compounds (rolipram, nitraquazone and xanthine derivatives, imidazo pyrido pyrazinones and 5-oxyindoles) was used to construct the binding site surrogate consisting of ®ve amino acid residues, a Zn 2 cofactor and an envelope of charged virtual particles. The model was validated by predicting the free energies of binding DG 0 pred of ten ligands (rolipram, imidazo pyrido pyrazinones and 5-oxyindoles). In seven cases the prediction was satisfactory. The rms deviation [4] in DG 0 is 0.16 and 1.82 kcalymol ±resulting in an uncertainty in IC 50 (or K i ) of 1.32 and 22.81 ±for the training and the test set respectively, while the corresponding maximal prediction errors in DG 0 pred were 0.27 kcalymol and 4.50 kcalymol.

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A Pharmacophore Model for PDE IV Inhibitors

Cited by 12 publications

References 11 publications

Synthesis of PDE IVb Inhibitors. 1. Asymmetric Synthesis and Stereochemical Assignment of (+)- and (−)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one

Synthesis of PDE IVb Inhibitors. 1. Asymmetric Synthesis and Stereochemical Assignment of (+)- and (−)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one

An Updated Topographical Model for Phosphodiesterase 4 (PDE4) Catalytic Site

A Peptidic Binding Site Model for PDE 4 Inhibitors

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