BMY 45778

BMY 45778 is a partial agonist of prostacyclin receptor [1].

Prostacyclin receptor (IP1) is a G-protein coupled receptor for prostacyclin. Prostacyclin inhibits platelet aggregation and elicits a potent vasodilation through binding to this receptor.

BMY 45778 is a partial agonist of prostacyclin receptor. BMY 45778 inhibited platelet aggregation with IC50 values of 35 nM, 136 nM and 1.3 μM in human, rabbit and rat, respectively. In human platelet membrane, BMY 45778 activated adenylyl cyclase with ED50 value of 6-10 nM and stimulated GTPase. Also, BMY 45778 completely inhibited the binding of Iloprost to platelet membranes with IC50 value of 7 nM. BMY 45778 inhibited iloprost-stimulated GTPase, which suggested that BMY 45778 is a partial agonist of prostacyclin receptor. In whole platelets, BMY 45778 increased cAMP levels and activated cAMP-dependent protein kinase [1]. BMY 45778 (1-10 μM) inhibited rat neutrophil aggregation induced by N-formyl-methionyl-leucylphenylalanine with IC50 value of 20 nM and inhibited the spontaneous activity of rat colon by 10-20%. Also, BMY 45778(10 μM) inhibited the inhibitory effect of cicaprost on rat colon [2].

References:
[1].  Seiler SM, Brassard CL, Federici ME, et al. [3-[4-(4,5-Diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid (BMY 45778) is a potent non-prostanoid prostacyclin partial agonist: effects on platelet aggregation, adenylyl cyclase, cAMP levels, protein kinase, and iloprost binding. Prostaglandins, 1997, 53(1): 21-35.
[2].  Wise H, Qian YM, Jones RL. A study of prostacyclin mimetics distinguishes neuronal from neutrophil IP receptors. Eur J Pharmacol, 1995, 278(3): 265-269.

[3-[4-(4,5-Diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid (BMY 45778) is a potent non-prostanoid prostacyclin partial agonist: effects on platelet aggregation, adenylyl cyclase, cAMP levels, protein kinase, and iloprost binding.[Pubmed:9068064]

Prostaglandins. 1997 Jan;53(1):21-35.

[3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid (BMY 45778) inhibits human (IC50 = 35 nM), rabbit (136 nM) and rat (1.3 microM) platelet aggregation. This compound activates adenylyl cyclase (ED50 = 6-10 nM) and stimulates GTPase in human platelet membrane preparations. The potency (EC50) of BMY 45778 stimulating adenylyl cyclase is comparable to iloprost. However, maximal stimulation of GTPase by BMY 45778 is approximately half the iloprost-stimulated activity, and BMY 45778 limits the GTPase stimulation by iloprost suggesting that BMY 45778 is a partial agonist at the IP receptor. BMY 45778 completely prevents [3H]]Iloprost binding to platelet membranes (IC50 = 7 nM). In whole platelets, BMY 45778 causes elevation of platelet cAMP levels (cAMP content doubles at 13 nM) and activation of the cAMP-dependent protein kinase (cAMP-protein kinase ratio is twice basal at 2 nM). BMY 45778 treatment of whole platelets also desensitizes the adenylyl cyclase activation by iloprost. These results indicate that BMY 45778, which is structurally different from prostacyclin and most prostacyclin agonists, acts by stimulating prostacyclin (IP) receptors.

Non-prostanoid prostacyclin mimetics as neuronal stimulants in the rat: comparison of vagus nerve and NANC innervation of the colon.[Pubmed:10683203]

Br J Pharmacol. 2000 Feb;129(4):782-90.

The spontaneous activity of the rat isolated colon is suppressed by prostacyclin analogues such as cicaprost (IC(50)=4.0 nM). Activation of prostanoid IP(1)-receptors located on NANC inhibitory neurones is involved. However, several non-prostanoids, which show medium to high IP(1) agonist potency on platelet and vascular preparations, exhibit very weak inhibitory activity on the colon. The aim of the study was to investigate this discrepancy. Firstly, we have demonstrated the very high depolarizing potency of cicaprost on the rat isolated vagus nerve (EC(50)=0.23 nM). Iloprost, taprostene and carbacyclin were 7.9, 66, and 81 fold less potent than cicaprost, indicating the presence of IP(1) as opposed to IP(2)-receptors. Three non-prostanoid prostacyclin mimetics, BMY 45778, BMY 42393 and ONO-1301, although much less potent than cicaprost (195, 990 and 1660 fold respectively), behaved as full agonists on the vagus nerve. On re-investigating the rat colon, we found that BMY 45778 (0.1 - 3 microM), BMY 42393 (3 microM) and ONO-1301 (3 microM) behaved as specific IP(1) partial agonists, but their actions required 30 - 60 min to reach steady-state and only slowly reversed on washing. This profile contrasted sharply with the rapid and readily reversible contractions elicited by a related non-prostanoid ONO-AP-324, which is an EP(3)-receptor agonist. The full versus partial agonism of the non-prostanoid prostacyclin mimetics may be explained by the markedly different IP(1) agonist sensitivities of the two rat neuronal preparations. However, the slow kinetics of the non-prostanoids on the NANC system of the colon remain unexplained, and must be taken into account when characterizing neuronal IP-receptors.

Nonprostanoid prostacyclin mimetics. 5. Structure-activity relationships associated with [3-[4-(4,5-diphenyl-2-oxazolyl)-5- oxazolyl]phenoxy]acetic acid.[Pubmed:7504734]

J Med Chem. 1993 Nov 26;36(24):3884-903.

cis-[3-[2-(4,5-Diphenyl-2-oxazolyl)ethenyl]phenoxy]acetic acid (3) was previously identified as a nonprostanoid prostacyclin (PGI2) mimetic that potently inhibits ADP-induced aggregation of human platelets with an IC50 of 0.18 microM. As part of an effort to further explore structure-activity relationships for this class of platelet inhibitor and to provide additional insight into the nonprostanoid PGI2 mimetic pharmacophore, the effect of constraining the cis-olefin moiety of 3 into various ring systems was examined. Incorporation of the cis-olefin of 3 into either an oxazole (26) or an unsubstituted pyrazole (35) heterocycle provided compounds that are equipotent with progenitor 3. However, the oxazole 11f, which is isomeric with 26, inhibits ADP-induced human platelet aggregation in vitro with an IC50 of 0.027 microM, 6-fold more potent than 3, 26, or 35. These results suggest that the central oxazole ring of 11f is functioning as more than a simple scaffold that provides optimal stereodefinition for interaction with the PGI2 receptor. The nitrogen atom of the central heterocycle of 11f is postulated to engage in hydrogen-bond formation with a donor moiety in the PGI2 receptor protein, an interaction not available to 26 due to the markedly different topology. In support of this contention, the crystal structures of 11f and 26 contain strong intermolecular hydrogen bonds between the carboxylic acid hydrogen atom and the nitrogen atom of the central oxazole ring. Although 11f and 26 are exact isosteres and could, in principle, adopt the same molecular packing arrangement in the solid state, this is not the case, and the intermolecular hydrogen-bonding interactions in 11f and 26 are accommodated by entirely different molecular packing arrangements. Incorporation of the olefin moiety of 3 into a benzene ring provided a compound, 40, over 60-fold weaker with an IC50 of 11.1 microM. The affinities of 11f, 26, 31, 32, and 40 for the human platelet PGI2 receptor, determined by displacement of [3H]iloprost, correlated with inhibition of platelet function. The solid-state structures of 11f, 26, 31, 32, and 40 were determined and revealed that the more potent compounds 11f and 26 adopt a relatively planar overall topography. In contrast, the central phenyl ring and the phenoxy ring of the weakly active compound 40 are rotated by 53 degrees from planarity. The chemical shifts of the protons of the phenoxy rings of 3, 11f, 18, 26, 31, 32, and 40 suggest that in solution 3, 11f, 18, and 26 adopt a planar conformation while 40 does not.(ABSTRACT TRUNCATED AT 400 WORDS)