(R)-Butaprost, free acid

Description

Butaprost is a structural analog of prostaglandin E₂ (PGE₂) with good selectivity for the EP₂ receptor subtype. Butaprost has frequently been used to pharmacologically define the EP receptor expression profile of various human and animal tissues and cells. Serious confusion as to the structure of butaprost was generated by Gardiner in 1986, when he reported that the epimer of butaprost showing this selective activity was the C-16 (R)-epimer (See reference 2 and NOTE). In order to increase the binding affinity of (R)-butaprost for prostanoid receptors, we removed the methyl ester of (R)-butaprost and re-established the natural C-1 carboxylic acid. Prostaglandin free acids generally bind to their cognate receptors with 10 to 100 times the affinity of the corresponding ester derivative. The pharmacology of (R)-butaprost has not been carefully studied, but it is generally considered to be the less active C-16 epimer. (NOTE: In the Gardiner paper in the 1986 British Journal of Pharmacology, butaprost appears on page 46 where it is given the name TR 4979. The structure as drawn is incorrect, in that the author was using and referring to the more active C-16 epimer, which is actually 16(S). The structure on page 46 shows the structure as 16(R). It was not until the late 1990’s that careful studies both in the US and Japan correctly identified the actual configuration of C-16 in the compound called butaprost is 16(S).)

Uses

Butaprost free acid is a selective prostaglandin E receptor (EP2) agonist with an EC50 of 33 nM and a Ki of 2.4 μM for murine EP2 receptor. Butaprost free acid is less activity against murine EP1, EP3 and EP4 receptors. Butaprost free acid attenuates fibrosis by hampering TGF-β/Smad2 signalling[1][2][3].

Definition

ChEBI: (r)-butaprost (free acid) is a prostanoid.

in vivo

References

[1] Yanbin Liang, et al. Upregulation of orphan nuclear receptor Nur77 following PGF(2alpha), Bimatoprost, and Butaprost treatments. Essential role of a protein kinase C pathway involved in EP(2) receptor activated Nur77 gene transcription. Br J Pharmacol. 2004 Jun;142(4):737-48. DOI:10.1038/sj.bjp.0705829
[2] Michael Schou Jensen, et al. Activation of the prostaglandin E 2 EP 2 receptor attenuates renal fibrosis in unilateral ureteral obstructed mice and human kidney slices. Acta Physiol (Oxf). 2019 Sep;227(1):e13291. DOI:10.1111/apha.13291
[3] K Tani, et al. Design and synthesis of a highly selective EP2-receptor agonist. Bioorg Med Chem Lett. 2001 Aug 6;11(15):2025-8. DOI:10.1016/s0960-894x(01)00359-6