The treatment of systemic sclerosis-related digital ulcers is challenging. Although the only effective drugs are prostacyclin analogs, their use is limited by vasodilation-related adverse reactions. In this study, we assessed the local iontophoresis administration of three soluble guanylate cyclase (A-350619 [3-[2-[(4-chlorophenyl)thiophenyl]-N-[4-(dimethylamino)butyl]-2-propenamide hydrochloride], SIN-1 [amino-3-morpholinyl-1,2,3-oxadiazolium chloride], and CFM 1571 [3-[3-(dimethylamino)propoxy]-N-(4-methoxyphenyl)-1-(phenylmethyl)-1H-pyrazole-5-carboxamide hydrochloride]) and two nonprostanoid prostaglandin I2 (prostacyclin) receptor agonists (MRE-269 [[4-[(5,6-diphenylpyrazinyl)(1-methylethyl)amino]butoxy]-acetic acid] and BMY 45778 [[3-(4,5-diphenyl[2,4'-bioxazol]-5'-yl)phenoxy]acetic acid]) to induce vasodilation onto the hindquarters of anesthetized rats. Skin blood flow was quantified using laser Doppler imaging during the whole experience, and safety was assessed by continuous recording of blood pressure and histopathological examination. Anodal iontophoresis of A-350619 (7.54 mM) induced a sustained increase in cutaneous blood flow (P = 0.008 vs. control). All other drugs exhibited poor or no effect on skin blood flow. Vasodilation with A-350619 iontophoresis was concentration-dependent (7.5, 0.75, and 0.075 mM; P < 0.001, Jonckheere-Terpstra trend test), and repeated administrations do not suggest any risk of tolerance. This study also compared continuous versus intermittent iontophoresis protocols. Continuous anodal iontophoresis of A-350619 at 7.5 mM increases cutaneous blood flow with good local tolerance. Iontophoresis of soluble guanylate cyclase stimulators should be investigated as potential local therapy for digital ulceration in patients with scleroderma.

01 May 2007·Prostaglandins & Other Lipid MediatorsQ3 · BIOLOGY

The effect of prostacyclin agonists on the differentiation of phorbol ester treated human erythroleukemia cells

Q3 · BIOLOGY

Article

Author: Wai Ming Kan ; Ching Yuh Chern ; Yu Lin Chen ; Huang Wei Shen

Phorbol-12-myristate-13-acetate (PMA) induces megakaryocytopoeisis in human erythroleukemia (HEL) cells which is characterized by the increase in cell size, increase in nuclear polyploidization and expression of megakaryocyte marker, CD41. However, upon treatment with 100 nM of selective prostacyclin (IP) agonist beraprost inhibits the induced differentiation. Moreover, selective non-prostanoid IP agonist, BMY 45778 prevents PMA induced megakaryocytopoeisis in HEL cells similarly, while prostaglandin E(2) and specific EP(3) agonist sulprostone have no effect. Thus, IP receptor is involved. Furthermore, adenylate cyclase activator forskolin and cAMP analog dibutyryl-cAMP also prevented PMA induced megakaryocytopoeisis in HEL cells. Thus, IP agonists inhibition of PMA induced megakaryocytopoeisis in HEL cells may involve a cAMP dependent pathway.

01 Nov 2002·Molecular PharmacologyQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Stoll, Friederike ; Schror, Karsten ; Holtje, Hans-Dieter ; Fuchs, Philip L. ; Liesener, Sven ; Hohlfeld, Thomas

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Preclinical	US	Bristol Myers Squibb Co.	01 May 2002

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