Synthesis of therapeutically useful prostaglandin and prostacyclin analogs

Collins, Paul W.; Djurić, Stevan W.

doi:10.1021/cr00020a007

Cited by 322 publications

(207 citation statements)

References 52 publications

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“…4A shows the prostacyclin analogs used in this study. Iloprost, cicaprost, and isocarbacyclin were reported to be potent agonists for the known prostacyclin receptor (20). Carbacyclin was synthesized first as an agonist, but its agonistic potency was relatively weak (20).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to iloprost, there are several stable prostacyclin analogs, including isocarbacyclin (20) 2␣ , PGD 2 , 6-hy-* This work was supported in part by the special coordination funds for promoting science and technology from the Science and Technology Agency of Japan and by a grant-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan. The costs of publication of this article were defrayed in part by the payment of page charges.…”

Section: Prostaglandins (Pgs)mentioning

confidence: 99%

“…High density binding was observed in the nucleus of the solitary tract (NTS) and in the spinal trigeminal nucleus in the lower brain stem as well as in the dorsal horn of the spinal cord. Much weaker but significant binding was found in various other regions of the brain such as the thalamus and cerebral cortex.In addition to iloprost, there are several stable prostacyclin analogs, including isocarbacyclin (20) 2␣ , PGD 2 , 6-hy-* This work was supported in part by the special coordination funds for promoting science and technology from the Science and Technology Agency of Japan and by a grant-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan. The costs of publication of this article were defrayed in part by the payment of page charges.…”

mentioning

confidence: 99%

“…In addition to iloprost, there are several stable prostacyclin analogs, including isocarbacyclin (20) droxydopamine, and kainate were purchased from Sigma. Cicaprost was from Prof. Gü nter Stock (Schering Aktiengesellschaft, Berlin).…”

mentioning

confidence: 99%

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A Novel Subtype of the Prostacyclin Receptor Expressed in the Central Nervous System

Takechi¹,

Matsumura²,

Watanabe³

et al. 1996

Journal of Biological Chemistry

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By use of several prostacyclin analogs and an in vitro autoradiographic technique, we have found a novel subtype of the prostacyclin receptor, one having different binding properties compared with those of the known prostacyclin receptor in the rat brain. Isocarbacyclin, which is a potent agonist for the known prostacyclin receptor, had high affinity for the novel subtype (dissociation constant (K d ) of 7.8 nM). However, iloprost, which is usually used as a stable prostacyclin analog, showed low affinity binding ( 3 H]iloprost also had high affinity in these regions, and the binding specificity was similar to that for the known prostacyclin receptor. Hemilesion studies of striatal neurons lesioned by kainate or of dopaminergic afferents lesioned by 6-hydroxydopamine revealed that the binding sites of the novel subtype exist on neuronal cells in the striatum, but not on the presynaptic terminal of afferents or on glial cells. Electrophysiological studies carried out in the CA1 region of the hippocampus revealed that prostacyclin analogs have a facilitatory effect on the excitatory transmission through the novel prostacyclin receptor. The widespread expression of the prostacyclin receptor in the central nervous system suggests that prostacyclin has important roles in neuronal activity. Prostaglandins (PGs)1 and thromboxane are formed from arachidonic acid by cyclooxygenase and the respective synthase for each PG, such as PGD synthase and PGI 2 synthase. These prostanoids exert a variety of functions through their specific membrane receptors coupled to G proteins not only in the peripheral organs, but also in the central nervous system. For example, PGD 2 acts as a sleep inducer (1, 2), produces hypothermia (3), inhibits luteinizing hormone-releasing hormone release (4), and is involved in biphasic modulation of pain sensation (5) and modification of olfaction (6). PGE 2 has hyperthermic (7), sedative (8), anticonvulsive (9, 10), and antidiuretic effects (11) and induces wakefulness (12, 13), stimulates luteinizing hormone-releasing hormone release (14), modifies pain (5, 9), and regulates food intake (11). Also, PGF 2␣ has an antidiuretic effect (15) and an inhibitory effect on oxytocin release (16). These three PGs are reported to be involved in the modulation of neurotransmitter release as well (17). Prostacyclin, discovered in 1976, is known to be a potent vasodilator and also to have an inhibitory effect on platelet aggregation (18). In the brain, however, it is not clear whether prostacyclin has specific functions or not. It seems that the chemical instability of prostacyclin and lack of knowledge about the prostacyclin receptor in the brain have hampered the investigation.Recently, we reported the presence and distribution of the prostacyclin receptor in the central nervous system by use of [ 3 H]iloprost, a stable prostacyclin analog, and an in vitro autoradiographic technique (19). High density binding was observed in the nucleus of the solitary tract (NTS) and in the spinal trigeminal nucleus in the lowe...

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Section: Resultsmentioning

confidence: 99%

Section: Prostaglandins (Pgs)mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A Novel Subtype of the Prostacyclin Receptor Expressed in the Central Nervous System

Takechi¹,

Matsumura²,

Watanabe³

et al. 1996

Journal of Biological Chemistry

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“…[1][2][3] Under physiological conditions, prostacyclin is a labile compound of limited clinical usage, 3 which has a half-life of approximately 3 minutes. In order to develop antithrombotic agents with better pharmacokinetic profile, Meanwell and co-workers [4][5][6][7][8] synthesized and evaluated a series of aromatic heterocyclic compounds (see compound 2 in Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Local intersection volume (LIV) descriptors: 3D-QSAR models for PGI2 receptor ligands

Martins¹,

Albuquerque²,

Alencastro³

2002

J. Braz. Chem. Soc.

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Prostaciclina I 2 inibe a agregação plaquetária pela interação com um receptor específico de membrana. Neste trabalho, desenvolvemos modelos de QSAR-3D para uma série de compostos heterocíclicos aromáticos usando como descritor o volume de interseção local. Os modelos obtidos podem ser aplicados no desenvolvimento de novos ligantes de receptor da PGI 2 com potencial atividade anti-agregante plaquetária.Prostacyclin I 2 inhibits platelet aggregation through specific binding to its membrane receptor. In this work, we developed 3D-QSAR models for a series of aromatic heterocyclic compounds from literature using the local intersection volume descriptor. The models obtained can be applied to design new PGI 2 receptor ligands with potential platelet anti-aggregating activity. Keywords: 3D-QSAR, local intersection volume (LIV), prostacyclin receptor, platelet aggregation IntroductionProstacyclin I 2 (PGI 2 ) (Figure 1) is an endogenous chemical mediator acting as a potent inhibitor of platelet aggregation, interacting with its specific receptor (IP) located on cellular membranes. [1][2][3] Under physiological conditions, prostacyclin is a labile compound of limited clinical usage, 3 which has a half-life of approximately 3 minutes. In order to develop antithrombotic agents with better pharmacokinetic profile, Meanwell and co-workers [4][5][6][7][8] synthesized and evaluated a series of aromatic heterocyclic compounds (see compound 2 in Figure 1). [4][5][6][7][8] Based on data from their research, we developed, in this work, 3D-QSAR models for ligands of IP receptor using the local intersection volume (LIV) descriptor, 9 i.e., the intersection volume between the volumes of the compound atoms and the volumes of a set of spheres of defined atom size. It composes a three-dimensional box, in analogy to the Grid method.10 The LIV-3D-QSAR models were obtained and evaluated by genetic algorithms (GA) and partial least squares (PLS) methods. [11][12][13] They can be applied to design new PGI 2 receptor ligands that could be potential inhibitors of blood platelet aggregation. Methods Steps on the LIV-3D-QSAR models developmentStep 1. Selection of 42 aromatic heterocyclic compounds 4-8 (see Table 1, Supplementary Material) divided in a training data set (30 compounds) and a test data set (12 compounds). The corresponding values of the biological activity 4-8 according to the pharmacological protocol established by Seiler and co-workers 14 are shown on Table 1.Step 2. Construction of a grid matrix composed by cubic unitary cells, where the vertices of the cells 4-8 and pharmacophoric sites (S1, S2, S3, and S4) definition according SAR studies. 5,20 817 Local Intersection Volume (LIV) Descriptors: 3D-QSAR Models Vol. 13, No. 6, 2002 correspond to the Cartesian coordinates of the eight carbon atoms. The vertices arrest lengths are 1.50Å (that is, almost equal to the carbon van der Waals radii of 1.54Å). The grid matrix is composed by a total of 2197 (13x13x13) carbon atoms, constructed on an Excel ® program, and imported into the...

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Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin by a Common Enantioselective Deprotonation Based Route

Vaulont

Gais²,

Reuter

et al. 1998

Eur. J. Org. Chem.

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Asymmetric total syntheses of 3‐oxacarbacyclin (4) and 3‐oxaisocarbacyclin (5) have been achieved by a new and common route. The key step of these syntheses is an enantioselective deprotonation of the prochiral ketone 25 with lithium (R,R)‐bis(phenylethyl)amide (12) in the presence of LiCl. Treatment of the thus formed enolate 26 with ClSiEt3 gave the enol ether 27 of 92% ee in 94% yield. Deprotonation of the analogous prochiral ketone 9 with 12 in the presence of LiCl followed by reaction of the enolate 13 with ClSiEt3 led to isolation of the silyl enol ether 8b of 92% ee in 95% yield. A study of the deprotonation of 9 with the chiral lithium amides 14−19 showed that 12 in combination with LiCl is the optimal base in terms of enantioselectivity and accessibility. The ω‐side chain in 4 and 5 was established by a Mukaiyama reaction of 27 with the unsaturated aldehyde 28, leading to ketone 39 of 90% de, in combination with a stereoselective Pd‐catalyzed allylic rearrangement of acetate 47 to the isomeric acetate 48 and a Mitsunobu reaction of the allylic alcohol 49. The key step in the construction of the α‐side chain in 4 is a Horner‐Wadsworth‐Emmons reaction of ketone 7c with the 8‐phenylnormenthol‐containing phosphonoacetate 56 which gave ester 60 of 90% de. Ester 60 was obtained diastereomerically pure by chromatography in 72% yield from 7c. Reduction of 60 furnished the allylic alcohol 62 which was converted to 4 in a standard fashion. It is at the stage of the α,β‐unsaturated ester 60 where divergence into synthesis of 5 was made. Selective isomerization of 60 to the β,γ‐unsaturated ester 66 of 97% ie in 91% yield was accomplished by deprotonation of 60 with 12 to enolate 65 and its subsequent regioselective protonation. By a similar reaction sequence the isomeric α,β‐unsaturated ester 61 was converted to the ß,γ‐unsaturated ester 69 of 97% ie in 88% yield. Reduction of 66 afforded the homoallylic alcohol 71 which was converted to 5 in a standard fashion.

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Synthesis of therapeutically useful prostaglandin and prostacyclin analogs

Cited by 322 publications

References 52 publications

A Novel Subtype of the Prostacyclin Receptor Expressed in the Central Nervous System

A Novel Subtype of the Prostacyclin Receptor Expressed in the Central Nervous System

Local intersection volume (LIV) descriptors: 3D-QSAR models for PGI2 receptor ligands

Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin by a Common Enantioselective Deprotonation Based Route

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