Discovery and SAR development of 2-(phenylamino) imidazolines as postacyclin receptor antagonists

doi:10.1016/j.bmcl.2003.10.070

Bioorganic & Medicinal Chemistry Letters

Volume 14, Issue 4, 23 February 2004, Pages 1053-1056

https://doi.org/10.1016/j.bmcl.2003.10.070 Get rights and content

Abstract

On the basis of screening hits (1a,b), a series of selective, high affinity prostacyclin receptor antagonists was developed. The optimized lead compound 25d [(4,5-dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxybenzyl)phenyl]amine] had analgesic activity in the rat.

The 2-(phenylamino)imidazoline 25d was found to be a high affinity, selective prostacyclin receptor antagonist which demonstrated analgesic activity in the rat.

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In order to achieve optimal responsiveness to prostanoid receptor agonists and antagonists, complete EGM-2 medium was diluted with serum-free EGM-2 to 10% and 30% in experiments that investigated angiogenic activation and inhibition, respectively. In these experiments the specific IP receptor antagonist CAY10441 (Clark et al., 2004) (also known as RO1138452 (Bley et al., 2006)) was used to test the involvement of the receptor in HUVEC migration and tube formation (Fig. 3A–D). Marked inhibition of HUVEC tube formation was readily apparent using phase-contrast microscopy (Fig. 3C and D).
Angiogenesis is regulated by numerous activators and inhibitors, including prostanoids. Although many studies have identified their roles in inflammation, regulatory functions of prostanoids in angiogenesis are poorly understood. Here, we compared the activation of angiogenesis in vitro by two prostanoids with important vascular roles: prostaglandin E₂ (PGE₂) – thought to be the most important prostanoid activator of angiogenesis – and prostaglandin I₂ (prostacyclin or PGI₂), whose receptors are predominantly expressed in endothelial cells. Both of these prostanoids activate G-protein coupled receptors: EP1, EP2, EP3 and EP4 by PGE₂ and IP by prostacyclin. Human umbilical vein endothelial cells (HUVECs) were used to characterize two pivotal pro-angiogenic processes in vitro: cell migration (using the matrigel droplet assay developed in our laboratory) and “tube formation” (a widely accepted method of assessing formation of blood vessel precursors). The suppression of cell migration and tube formation by the IP-specific antagonist CAY10441 was more extensive (~ 80%) than by the EP4-specific antagonist L-161,982 (~ 20%). AH6809, an antagonist of EP1, EP2 and EP3 receptors did not significantly suppress angiogenesis. Expression of the pro-angiogenic receptors KDR and Tie-2 in HUVECs was preferentially suppressed by antagonism of IP and EP4 receptors, respectively. EP4 and IP receptor agonists elicited biphasic actions on angiogenic processes in which there was activation at low concentration, and rapid desensitization at high concentrations — a characteristic common to many G-protein coupled receptors. Together these findings suggest that the prostacyclin-IP pathway plays a major role in the regulation of pro-angiogenic processes in HUVECs.
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However, it remains to be determined if either the prostaglandin I2/prostanoid IP system or the prostaglandin E2/prostanoid EP2 receptor system plays an important role in the vasodilator effects of NO on retinal blood vessels. To determine the role of the prostaglandin I2/prostanoid IP receptor system in the NO-mediated retinal vasodilatory mechanism, we examined the effects of 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imadazol-2-amine (CAY10441), an antagonist of the prostanoid IP receptor (Clark et al., 2004), and 9α,11α-azoprosta-5Z,13E-dien-1-oic acid (U-51605), an inhibitor of prostaglandin I2 synthase (Gorman et al., 1979), on vasodilation of rat retinal arterioles induced by the NO donor (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3) in vivo. We also determined whether the NO/cyclooxygenase-1/prostaglandin I2 axis is present in human retinal vascular endothelial cells.
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^†: Current address: Neurogen, 35Northeast Industrial Park Road, Branford, CT 06405, USA.

^‡: Current address: NeurogesX, San Carlos Business Park, 981F Industrial Road, San Carlos, CA 94070-4117, USA.

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Discovery and SAR development of 2-(phenylamino) imidazolines as postacyclin receptor antagonists

Abstract

Trends Pharmacol. Sci.

Prostaglandins

Br. J. Pharmacol.

Nature

Exp. Opin. Invest. Drugs

Br. J. Pharmacol.

Br. J. Pharmacol.

Life Sci.