Konzett assay

A similar study of Cu substitution was carried out by a Wyeth team (113.124.125) who found cyano to be the only group of interest. In their assay (Konzett, histamine agonist, aerosol administration), lla-cyano-ll-deoxy-PGE2 had 1% and the 15(R/S)-methyl derivative (II) 10% the activity of I-PGE2. The cyano group, as well as the methyl group, also were effective llct-sub-stituents in the PGF2p series (see section C). 

The significance of the 11- and/or 15-hydroxy functions for bronchodilator activity is demonstrated in Table VI. Substantial activity clearly obtains in the 11-deoxy series, but the 15a-hy-droxy group apparently is an essential feature, although this requirement can be satisfied by a hydroxy group at Cje see section VIII F. Nevertheless it is noteworthy, that in the Konzett as well as other assays, even a primitive prostaglandin such as 11,15-bisdeoxy-PGEi produces a real PG-like effect, albeit with much diminished potency. 

Muchowski and co-workers have described the synthesis and bronchodilator activity of a series of ring halogenated prostaglandins. Several of these compounds showed excellent activity in the Konzett assay (ys. histamine) on intravenous or aerosol administration (Table X). Phase I evaluation of the most potent member of the series, 9-deoxy-9p-fluoro-PGE2 (IX), however, revealed a cough liability which precluded further clinical investigation (126,130). 

In our Konzett assay, ll-deoxy-16-methyl derivatives showed exceptionally high potency (48), an observation also made by a Wyeth group (113). However, Turther examination of 11-deoxy-16(R/S)-methyl-PGEi (XXIV) in the pilocarpine dog assay indicated this compound to be relatively ineffective and of no interest. Another member of this series, 16(S)-methyl-20-methoxy-PGE2 (XXV, YPG-209), has been reported to be 230 times as potent as PGE2 in the guinea pig vs. histamine-induced spasms. It also is claimed to be orally effective in this model without concommitant hypotension or diarrhea (169). This is the first claim, that we are aware of, for oral activity for any prostaglandin bronchodilator and we await the results of further studies with this compound. 

Since all eight failures apparently were selected, at least in part, on the basis of data obtained from a guinea pig Konzett-Rossler assay, the question arises as to the predictive capability of this widely used model for the selection of effective prostaglandin bronchodilators. However, in point of fact, four of the failures (entries 2-5) provided relatively modest Konzett responses, about 1-20% that of 1-PGEi, and therefore only one of these compounds (3) can be considered to have been tested at an appropriate multiple of the apparent 1-PGEi minimally effective dose [(50-100 jq)10.11.1641. Accordingly, the possibility remains that "weak" candidates may not have been studied at sufficiently high dose levels. 

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