Nileprost

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.

The ability of prostaglandin (PG) analogs [iloprost (I), nalador (II), nileprost (III), flunoprost(IV), and U46619 (V)] to prolong the allograft survival of mouse skin without immunosuppressants was determinedI was the most effective compound on proximal and distal allograft transplants.II retarded the rejection in the proximal allograft and IV prolonged the survival of the distal allograft; III and V had no effect.Dexamethasone (DEX) the standard prolonged both grafts, especially the distal allograft.Skin contents of TXB₂ and PGF_2α decreased with applications of I, II and III.DEX had no effect on TXB₂ and PGF_2α levels but increase PGE content.IV and V increased TXB₂ and PGF_2α levels.These results do not support the importance of thromboxane for the monitoring of skin allograft rejection as has been seen for heart allografts.What may be more important is the increase of PGE in the regenerated skin as observed with DEX actions.