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This is very strange. The non-confidential presentation is from the sponsor of the drug, Engrail Therapeutics, so the stereochemistry should be correct. However the WO2023130117A1 patent application only discloses the R,R enantiomer (CAS 2950168-16-6). To summarize:
ENX-104/105 Disclosures
Enantiomer
Patent
CAS Regno
Non-confidential presentation
2R,3R
WO-2023/130117: Example 1
2950168-16-6
ENX-105
2S,3S
WO-2023/130119: Example 1
Not registered
ENX-104
Furthermore, of the two enantiomers, only ENX-104 is listed in the Engrail Therapeutics company pipeline. While it is possible that there is another patent application that has not yet published and that claims the 2S,3S enantiomer, it would be highly unusual that a company would disclose the structure of a drug candidate before the patent application claiming it has published. Therefore it appears that the stereochemistry listed in the companies non-confidential presentation for ENX-104/105 is reversed from what it should be.
That is very confusing indeed. Thanks for investigating this.
Looking a little myself, it seems that they are developing both enantiomers and both are currently in preclinical development but ENX-105 is "a few months behind" ENX-104. See [1], [2], and [3]. However, a phase 1 trial of ENX-104 looks to be starting very soon ([4]).
Looking at the pharmacology, both ENX-105 and nemonapride are said to be significant 5-HT1A receptor agonists, whereas ENX-104 is described as selective for the D2-like receptors and having "little or no functional activity" at the 5-HT1A receptor. This seems to suggest that ENX-105 may be more similar to nemonapride than ENX-104 and that the presentation stereochemistry may actually be correct. That said, the deuteration might also modify things though. – 76.174.0.57 (talk) 05:55, 24 October 2024 (UTC)[reply]
OK, I think I have figured it out. It turns out that Engrail has filed another patent application (WO-2023/130119; now added to the above table) that claims the enantiomer. What was confusing is that while CAS Scifinder lists the patent, they had not registered all the compounds within the patent, hence the enantiomer has not yet been assigned a CAS Regno and I could not find by searching for the structure. But I could find by searching for the assignee. Now that we know both entantiomers are claimed in published patent applications, it appears that the non-confidential presentation is correct. I will swap the strutures in File:ENX-104.svg and File:ENX-105.svg and correct the data in the infobox. Boghog (talk) 10:15, 24 October 2024 (UTC)[reply]
I think we will have to await for more secondary sources. One thing I can say for sure is that nemonapride was originally made as a combination of all four possible isomers and I suspect that when scientists at Yamanouchi found out that the cis isomer (i.e. 2S,3S in mixture with 2R,3R = a racemic mixture), they probably focused on that for development as their marketed drug. It is always much more expensive to produce chiral drugs unless you are "lucky" and can find an already-chiral natural product to use as an intermediate. There is no doubt (see the 2017 publication doi:10.1248/cpb.c16-00568) that the useful biological activity of nemonapride lies in its (+)-(2R,3R) isomer. The Engrail presentation is interesting. The author chooses to draw (p.18) racemic nemonapride in the 2S,3S form but that's a little disingenuous since as any chemist knows that both 2S,3S and 2R,3R are present in racemates. I conclude from that presentation that ENX-104 is racemic and that Engrail then investigated its chiral components and found that the 2R,3R isomer ENX-105 was a better drug since it lost some of the unwanted side-effects caused by the 2S,3S form. However, they would find that much more expensive to manufacture, so for the moment I think we have to wait to see what they attempt to register and sell. Incidentally, 76.174.0.57 please register an account: it is impossible to WP:PING you to Talk Pages unless you do so and I'm sure many other editors here will want to do that given how productive you have been. Thanks for all your contributions so far. Mike Turnbull (talk) 10:59, 24 October 2024 (UTC)[reply]
@BoghogAs of this revision today the drugbox shows the 2S,3S form as one way of drawing the racemate ENX-104. However, in view of my comments above, I think it would be better to use your ENX-105 drawing in the drugbox. That's another possible version of the racemate by standard chemical conventions in the absence of markers indicating absolute stereochemistry but is, in my opinion, where all the useful biology lies. We could add an image caption to emphasise that this is racemic. If you agree, please make that change. Mike Turnbull (talk) 11:49, 24 October 2024 (UTC)[reply]
The patent applications WO-2023/130117 and WO-2023/130119 describe the synthesis of the 2R,3R and 2S,3S enantiomers, respectively, starting from the chiral starting materials Boc-L-alanine and Boc-D-alanine. These starting materials are relatively inexpensive, making the enantioselective synthesis cost-effective. The claims in both patents focus on diastereomerically and enantiomerically enriched compounds (>90%). There is no mention in the Engrail patent application of the preparation of a racemic mixture, nor has the racemate been registered with CAS. Thus, I conclude that ENX-104 is optically pure, not a racemate. Boghog (talk) 12:37, 24 October 2024 (UTC)[reply]
OK, let's leave it as-is for now. I must say I find it weird that according to the data in both patents (e.g. for the D2S binding) both RR and SS nemonapride are very potent binders. It is very unusual for both enantiomers of a compound to have similar activities. Mike Turnbull (talk) 13:36, 24 October 2024 (UTC)[reply]
