Prostacyclin‐analogs

Nickolson, Robert; Town, M.-H.; Vorbrüggen, Helmut

doi:10.1002/med.2610050102

Cited by 94 publications

(27 citation statements)

References 201 publications

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“…Prostacyclin is relatively unstable, with a half-life in aqueous solution of 3-5 min (38). The synthetic analogs used in the current study are more stable.…”

Section: Discussionmentioning

confidence: 92%

Prostacyclin Analogs Inhibit Fibroblast Contraction of Collagen Gels through the cAMP-PKA Pathway

Kamio

Liu

Sugiura

et al. 2007

Am J Respir Cell Mol Biol

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Prostacyclin is an arachidonic acid metabolite that modulates vascular tone within the lung. The current study evaluated the hypothesis that prostacyclin can also modulate tissue remodeling by affecting fibroblast-mediated contraction of extracellular matrix. To accomplish this, fibroblasts were cultured in three-dimensional native type I collagen gels in the presence of prostacyclin analogs: carbaprostacyclin, iloprost, and beraprost. All three analogs significantly inhibited contraction of the three-dimensional collagen gels mediated by three different fibroblasts. All three analogs significantly inhibited fibronectin release and reduced fibroblast fibronectin mRNA expression. Addition of exogenous fibronectin restored the contractile activity to fibroblasts incubated in the presence of all three analogs. Iloprost and beraprost significantly activated cAMP-dependent protein kinase-A (PKA), and an action through this pathway was confirmed by blockade of the inhibitory effect on contraction and fibronectin release with the PKA inhibitor KT-5720. In contrast, carbaprostacyclin, which is not as selective for the prostacyclin (IP) receptor, did not activate PKA, and its effects on contraction and fibronectin release were not fully blocked by KT-5720. Finally, the cAMP analogs N 6 -Benzoyl-(6-Bnz-) cAMP and dibutyryl-cAMP inhibited contraction, and this contrasted with the activity of an Epac selective agonist 8-pCPT-2-O-Me-cAMP, which had no effect. Taken together, these results indicate that prostacyclin, acting through the IP receptor and by activating PKA, can lead to inhibition of fibronectin release and can subsequently inhibit fibroblastmediated collagen gel contraction. The ability of prostacyclin to modulate fibroblast function suggests that prostacyclin can contribute to tissue remodeling.

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“…Prostacyclin is relatively unstable, with a half-life in aqueous solution of 3-5 min (38). The synthetic analogs used in the current study are more stable.…”

Section: Discussionmentioning

confidence: 92%

Prostacyclin Analogs Inhibit Fibroblast Contraction of Collagen Gels through the cAMP-PKA Pathway

Kamio

Liu

Sugiura

et al. 2007

Am J Respir Cell Mol Biol

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“…Several groups have previously attempted to define a pharmacophore for prostacyclin receptor agonists (Tsai et al, 1991; Meanwell et al, 1993a,b), and structure-activity relationships have been described in great detail for both types of compounds (Skuballa and Vorbruggen, 1983;Nickolson et al, 1985;Armstrong et al, 1986;Tsai and Wu, 1989;Meanwell et al, 1992a Meanwell et al, ,b,c, 1993a Meanwell et al, ,b, 1994aJones et al, 1993;Muir et al, 1993), but no pharmacophore that integrates both groups of compounds has previously appeared.…”

Section: Introductionmentioning

confidence: 99%

“…2, the skeletons of the nonprostanoid IP receptor agonists differ considerably. In some compounds, putative hydrogen bond acceptors such as heterocycles (i.e., oxazole) or oxime groups serve instead of the hydroxyl groups.Several groups have previously attempted to define a pharmacophore for prostacyclin receptor agonists (Tsai et al, 1991; Meanwell et al, 1993a,b), and structure-activity relationships have been described in great detail for both types of compounds (Skuballa and Vorbruggen, 1983;Nickolson et al, 1985;Armstrong et al, 1986;Tsai and Wu, 1989;Meanwell et al, 1992a Meanwell et al, ,b,c, 1993a Meanwell et al, ,b, 1994aJones et al, 1993;Muir et al, 1993), but no pharmacophore that integrates both groups of compounds has previously appeared.Correlation of the previous attempts in conjunction with incorporation of new compounds of different structural classes were united into a common agonistic pharmacophore. Extensive conformational searching was required in the absence of a rigid lead compound.…”

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confidence: 99%

Pharmacophore Definition and Three-Dimensional Quantitative Structure-Activity Relationship Study on Structurally Diverse Prostacyclin Receptor Agonists

Stoll

Liesener²,

Hohlfeld³

et al. 2002

Mol Pharmacol

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Prostacyclin is an endogenous mediator that shows potent platelet inhibitory activity and powerful relaxation of peripheral resistance vessels. Prostacyclin receptor agonists are valuable drugs in the treatment of various vascular diseases spanning primary pulmonary hypertension to Raynaud's syndrome. Although agonists from various structural classes were synthesized, a common pharmacophore was never defined. Therefore, an attempt was made to integrate the different agonists into a single model. A dataset of structurally diverse prostacyclin receptor agonists was tested for its affinity to the human platelet prostacyclin receptor. The dataset included prostanoid and nonprostanoid ligands comprising iloprost, cicaprost, and BMY45778. Extensive conformational analyses were performed for both classes of compounds because of the absence of rigid templates. The search and superimposition procedure yielded a pharmacophore that aligns the essential carboxylate group of the agonists as well as demonstrates that different functional groups in prostanoid and nonprostanoid agonists can be arranged in a uniform conformation. A three-dimensional quantitative structure-activity relationship study was performed using the programs GRID and GOLPE. This analysis yielded a cross-validated correlation coefficient of 0.77. With this model, it is possible to predict the affinity of untested compounds.Prostacyclin (PGI 2 ), an endogenous mediator, is synthesized primarily in the vascular endothelium. It plays an important role in the regulation of blood flow; it is a potent vasodilator and inhibits platelet aggregation. Both actions are mediated by a specific G-protein coupled receptor, the prostacyclin receptor (IP receptor). The binding of PGI 2 to this receptor leads to the coupling of G s protein to adenylate cyclase and subsequent elevation of intracellular cAMP levels.PGI 2 is a clinically useful agent for the precise control of platelet function. Its use is impaired by its instability: the enol ether linkage of PGI 2 is spontaneously hydrolyzed with a half-life of 3 min (Stehle, 1982;Armstrong, 1996), limiting therapeutic application to parenteral administration. Much effort was therefore directed toward developing metabolically stable and orally available IP-receptor agonists. These can be divided into two groups: the so-called prostanoid agonists preserve the characteristic structural features found in PGI 2 , namely the carboxylate group and hydroxyl functions at C-9 and C-15 (see Fig. 1), whereas the nonprostanoid agonists do not show any structural similarities with PGI 2 except for the essential carboxylate group. As can be seen in Fig. 2, the skeletons of the nonprostanoid IP receptor agonists differ considerably. In some compounds, putative hydrogen bond acceptors such as heterocycles (i.e., oxazole) or oxime groups serve instead of the hydroxyl groups.Several groups have previously attempted to define a pharmacophore for prostacyclin receptor agonists (Tsai et al., 1991; Meanwell et al., 1993a,b), and structure...

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“…[7][8][9]. Metabolic stability has been conferred upon prostacyclin derivatives by the incorporation of a wide variety of structural modifications into the upper (a) and lower (o) side chains (7)(8)(9). It occurred to us that the prostacyclin analogue 2 was a particularly attractive synthetic target because of the minimal acid sensitivity, good chemical stability, and marked preference for the hydrogen bonded Z isomeric form associated with the vinylogous amide functionality (10,11).…”

mentioning

confidence: 99%

“…(for reviews on this subject, see refs. [7][8][9]. Metabolic stability has been conferred upon prostacyclin derivatives by the incorporation of a wide variety of structural modifications into the upper (a) and lower (o) side chains (7)(8)(9).…”

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confidence: 99%

(±)-4-Oxo-9-deoxy-9-azaprostaglandin I₂ derivatives. Very stable prostacyclin analogs

Guzmán¹,

Martinez²,

Velarde³

et al. 1987

Can. J. Chem.

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The synthesis of 4-oxo-9-deoxy-9-azaprostaglandin I2 (23a) and two ω-chain analogues thereof (23c and 23e) is described. The most salient features of the synthetic process used were (a) introduction of the nitrogen functionality at C-9 by [3,3] sigmatropic rearrangement of the trichloroacetamidate 5b to the trichloroacetamide 6, (b) transformation of 6 into the bicyclic lactam 7 with sodium borohydride, (c) stereospecific introduction of the 11α-hydroxyl group via the bromohydrin 8a, and (d) attachment of the α chain by extrusion of sulfur from the thioimidates 20 by the Eschenmoser sulfide contraction process.

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Prostacyclin‐analogs

Cited by 94 publications

References 201 publications

Prostacyclin Analogs Inhibit Fibroblast Contraction of Collagen Gels through the cAMP-PKA Pathway

Prostacyclin Analogs Inhibit Fibroblast Contraction of Collagen Gels through the cAMP-PKA Pathway

Pharmacophore Definition and Three-Dimensional Quantitative Structure-Activity Relationship Study on Structurally Diverse Prostacyclin Receptor Agonists

(±)-4-Oxo-9-deoxy-9-azaprostaglandin I₂ derivatives. Very stable prostacyclin analogs

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Prostacyclin‐analogs

Cited by 94 publications

References 201 publications

Prostacyclin Analogs Inhibit Fibroblast Contraction of Collagen Gels through the cAMP-PKA Pathway

Prostacyclin Analogs Inhibit Fibroblast Contraction of Collagen Gels through the cAMP-PKA Pathway

Pharmacophore Definition and Three-Dimensional Quantitative Structure-Activity Relationship Study on Structurally Diverse Prostacyclin Receptor Agonists

(±)-4-Oxo-9-deoxy-9-azaprostaglandin I2 derivatives. Very stable prostacyclin analogs

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(±)-4-Oxo-9-deoxy-9-azaprostaglandin I₂ derivatives. Very stable prostacyclin analogs