An improved synthesis of the selective EP4 receptor agonist ONO-4819.

An improved synthesis of the highly selective EP4-receptor agonist ONO-4819 has been developed. The previous synthesis suffered from several drawbacks, in which a critical one is the difficulty in the removal of byproducts leading to unsatisfactory quality of the active pharmaceutical ingredient (API). Furthermore, on stereoselective reduction of an enone intermediate by binaphthol-modified lithium aluminum hydride, low concentration of the reaction conditions and tedious purification procedures to remove excess binaphthol were critical issues for the manufacturing process of the API. In the improved process, we have developed improved conditions using gamma-thiobutyrolactone as sulfur source instead of potassium thioacetate to introduce the sulfur-containing C4 side chain without formation of byproducts. For stereoselective synthesis of the chiral alcohol, (-)-DIP-chloride reduction is found to be the best method, which can improve not only the enantioselectivity but also the workload for removing the chiral modifier in a purification process. Furthermore, benzoyl and tert-butyldimethylsilyl groups as protecting groups for hydroxyl functions were used for precise process controls of all intermediates. By changing these protecting groups, the purity of ONO-4819 was strictly controlled through crystalline intermediates. Thus, an improved robust process for ONO-4819 with a high chemical purity was developed.

Design and synthesis of a selective EP4-receptor agonist. Part 4: practical synthesis and biological evaluation of a novel highly selective EP4-receptor agonist.

A practical method of synthesizing a highly selective EP4-receptor agonist 1 using Corey lactone 2 as a key intermediate was developed. Selective methanesulfonylation of the primary alcohol of the diol 8 under the newly devised conditions followed by the protection of the remaining secondary alcohol are key reactions in this new method. Further biological evaluation of 1a-b is also reported.

Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-phenyl-5-thiaPGE(1) and 9-beta-halo derivatives with improved stability.

To identify a new selective EP4-agonist with improved chemical stability, further chemical modification of those reported previously was continued. We focused our attention on chemical modification of the alpha chain of 3,7-dithiaPGE(1) and selected 5-thiaPGE(1) as a new chemical lead. Introduction of an optimized omega chain to the 5-thiaPG skeleton afforded m-methoxymethyl derivative 33a, which showed the most potent EP4-receptor agonist activity and good subtype-selectivity both in vitro and in vivo. 9beta-HaloPGF derivatives were also synthesized and biologically evaluated in an attempt to block self-degradation of the beta-hydroxyketone moiety. Among these series, and 39b showed potent agonist activity and good subtype-selectivity. Structure-activity relationships (SARs) are also discussed.

Design and synthesis of a selective EP4-receptor agonist. Part 1: discovery of 3,7-dithiaPGE1 derivatives and identification of their omega chains.

Improvement of EP4-receptor selectivity and the agonist activity by introduction of heteroatoms into the alpha chain of PGE1 was investigated. Among the compounds tested, 3,7-dithiaPGE1 4a exhibited good EP4-receptor selectivity and agonist activity. Further modification of the omega chain of 3,7-dithiaPGE1 was performed to improve EP4-receptor selectivity and agonist activity. Of the compounds produced, 16-phenyl-omega-tetranor-3,7-dithiaPGE1 4p possessing moderate EP4-receptor selectivity and agonist activity, was identified as a new chemical lead for further optimization by modification of the aromatic moiety.

Design and synthesis of a selective EP4-receptor agonist. Part 2: 3,7-dithiaPGE1 derivatives with high selectivity.

To identify new highly selective EP4-agonists, further modification of the 16-phenyl moiety of 1 was continued. 16-(3-methoxymethyl)phenyl derivatives 13-(6q) and 16-(3-ethoxymethyl)phenyl derivatives 13-(7e) showed more selectivity and potent agonist activity than 1. 16-(3-methyl-4-hydroxy)phenyl derivative 18-(14e) demonstrated excellent subtype selectivity, while both its receptor affinity and agonist activity were less potent than those of 13-(6q). Structure-activity relationships (SARs) are also discussed.