Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Elsevier Journal Backfiles on ScienceDirect (DFG Nationallizenzen)
Beschreibungen/Notizen
A series of prostaglandin DP agonists containing a 3-oxa-15-cyclohexyl motif was synthesized and evaluated in several in vitro and in vivo biological assays. The reference compound
ZK 118.182 (9β-chloro-15-cyclohexyl-3-oxa-ω-pentanor PGF
2α) is a potent full agonist at the prostaglandin DP receptor. Saturation of the 13,14 olefin affords
AL-
6556, which is less potent but is still a full agonist. Replacement of the 9-chlorine with a hydrogen atom or inversion of the carbon 15 stereochemistry also reduces affinity. In in vivo studies
ZK 118.182 lowers intraocular pressure (IOP) upon topical application in the ocular hypertensive monkey. Ester, 1-alcohol, and selected amide prodrugs of the carboxylic acid enhance in vivo potency, presumably by increasing bioavailability. The clinical candidate
AL–
6598, the isopropyl ester prodrug of
AL-
6556, produces a maximum 53% drop in monkey IOP with a 1 μg dose (0.003% w/w) using a twice-daily dosing regime. Synthetically,
AL–
6598 was accessed from known intermediate
1 using a novel key sequence to install the
cis allyl ether in the α chain, involving a selective Swern oxidative desilylation of a primary silyl ether in the presence of a secondary silyl ether. In this manner, 136
g of
AL–
6598 was synthesized under GMP conditions for evaluation in phase I clinical trials.
Graphic