Hisao Nakai

Diisobutylaluminum 2,6-di-t-butyl-4-methylphenoxide. Novel stereoselective reducing agent for prostaglandin synthesis.

In an effort to explore the selective reducing agents suitable for prostaglandin synthesis, diisobutylaluminum 2,6-di-t-butyl-4-methylphenoxide (1) is found to be among the best. Reduction of the C-15 ketone with 1 in toluene at −78 °C produced the desired 15S-alcohol in 95% yield with 92% stereoselectivity. The present procedure is suitable for the synthesis of prostaglandin derivatives and related polyfunctional natural products as shown in the conversion of PGE2 methyl ester to PGF2α methyl ester in 95% yield and 100% selectivity.

Design and synthesis of a highly selective EP2-receptor agonist

EP2-receptor selective agonist 3 was identified by the structural hybridization of butaprost 1a and PGE(2) 2a. Based on this information, a chemically more stabilized 4 was discovered as another highly selective EP2-receptor agonist, iv administration of which to anesthetized rats suppressed uterine motility, while PGE(2) 2a stimulated uterine motility.

Pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines and their tricyclic derivatives as corticotropin-releasing factor 1 (CRF1) receptor antagonists

To identify structurally novel CRF1 receptor antagonists, a series of bicyclic core antagonists, pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines, imidazo[1,2-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines were designed, synthesized and evaluated as CRF1 receptor antagonists. Compounds 2-27 showed binding affinity (IC(50)=4.2-418 nM) and antagonist activity (EC(50)=4.0-889 nM). Compound 5 was found to show oral efficacy in an Elevated Plus Maze test in rats. Further chemical modification of them led us to discovery of the tricyclic core antagonists pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidines. The discovery process of these compounds is presented, as is the study of the structure-activity relationship.

Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-phenyl-5-thiaPGE1 and 9-β-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 highly selective EP4-receptor agonist. Part 1: 3,7-dithiaPG 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.

Highly potent inhibitors of TNF-α production. Part II: Metabolic stabilization of a newly found chemical lead and conformational analysis of an active diastereoisomer

Design and synthesis of metabolically stabilized inhibitors of TNF-alpha production, which could be new drug candidates, are reported. Conformational analysis of an active diastereoisomer was performed based on biological evaluations of the conformationally fixed indane derivatives 17 and 18. Structure-activity relationships (SARs) based on biological evaluations of the optically active derivatives are also discussed. Full details including chemistry are reported.

Non-peptidic inhibitors of human neutrophil elastase: The design and synthesis of sulfonanilide-containing inhibitors

A novel series of pivaloyloxy benzene derivatives has been identified as potent and selective human neutrophil elastase (HNE) inhibitors. Convergent syntheses were developed in order to identify the inhibitors which are intravenously effective in an animal model. A compound of particular interest is the sulfonanilide-containing analogues. Structure-activity relationships are discussed. Structural requirements for metabolic stabilization are also discussed.

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.

Development of a highly selective EP2-receptor agonist. Part 1: identification of 16-hydroxy-17,17-trimethylene PGE2 derivatives.

Design and synthesis of an EP2-receptor selective agonist began with the chemical modification of alpha- and omega-chains of butaprost 1a, which exhibits an affinity for the IP-receptor. Two series of prostaglandin (PG) analogues with a 16-hydroxy-17,17-trimethylene moiety as an omega-chain were identified. Among those tested, 4a,b,e,f,h and 6a,b,e,f,h were found to be highly selective EP2-receptor agonists. Structure-activity relationships are discussed.

Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists.

To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of γ-lactam prostaglandin E analogs bearing a 16-phenyl ω-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration.