jdoe2020's comments

Yes but many people that have had kids get Alzheimer's. AD isnt aggressively selected against because it is only deleterious past reproductive age.

It's true but AD is likely not one disease but is many different mutations causing a family of shared symptoms which makes it hard to study. It's often better to gain a mechanistic understanding in a reductive model because you'd not have the statistical power in a mixed population to see anything at all.

This is really good point. People underestimate he degree failed trials have value in understanding the basic science behind diseases, especially mechanistically complex ones.

I mean for AD it could perhaps be useful (of course it would not work for most other diseases) but legally that is very dicey because of informed consent. TBH we are not even sure if AD is one even one disease or if it multiple masquerading as one. We aren't even sure if amalyoid beta is a major contributor or cause. Or if it is an effect of the disease. The field is fraught with controversy and even seminal papers have been retracted. But getting back to that lack of understanding of the root cause this is why mice are useful, if we have a reproducible AD like phenotype in a transgenic mouse line that gives us some fundamental understanding of the underlying disease process in a way that likely wouldn't be possibly in a possibly polymorphic human disease population.

You can also dose the mice at the same point in the disease process which is very useful in getting statistical significance for an effect.

I also don't think you'd get enough people and they would be spread out all over the country. Hard to administer your proprietary drug in 100 different nursing homes. Much easier to walk down the mouse facility in the basement

Yeah I was looking for that but didn't find it in the paper, someone else here linked to pubchem in this thread.

It's 3-(4-pyridinyl)-2-(napthylmethyl)-pyrazole N-oxide or something like that. My IUPAC is a bit rusty

Shouldn't be too bad. My gut would be toa naphthalene acetic acid ester, treat with LDA, add (4-pyridinyl)acetaldehyde to get a diketone by claisen-type condensation, then treat with hydroxylamine then reflux with hydrazine to form the pyrazole not sure how you would get the n-oxide but there is likely a selective oxidant available.

The n oxide kind of scares me a bit. Seems like it could have some interactions with liver enzymes. Usually you avoid them if you can.

Also you can cut them open when you are done. Can't do that to people. Sometimes you need biochemical tests and imaging very quickly post mortem to avoid changes in protein postranslational modifications. This is particularly important in AD studies. We needed to kill the mice and have their hippocampi in a grinder with phosphatase inhitor in under 10 minutes.

Then your get dropout problems and by the time there is an effect you don't have the statistical power to detect it. You need 3-6 months on an AD, psychiatic, metabolic, or autoimmune drug to see a Real effect so that is how long you must wait to ramp the dose. It could take years to go from a conservative guaranteed nontoxic dose to an effective one. But in that time most patientss will have gotten tired of waiting and switched drugs, moved to a new city and dropped out of the trial, or die. Sure it could work for some things like antimicrobials or erectile dysfunction drugs that have a rapid response, but that isn't where most of the drug development is. It is in those categories I listed.

I work in the side of academia that feeds drug leads to pharma and have seen this process.

The big problem aside from time is cost and scale. You might start with either a million compound in silico 10000 compounds in a high throughout enzyme screening program. You might get 500 hits with reasonable affinity which you put those in cell cultures and get 50 compounds. Then you go a small scale mouse study and may get 5-10 decent hits that don't have very obvious tox issues. Then you do a large mouse study of those for efficacy. You will get 1-2 compounds that may be suitable to go into people and there is maybe a 10% chance you get through phase III and onto the market. Usually there is also a step in monkeys before it goes into people.

The main issue here is that at each of those steps the cost scales 10-100x so you really, really need cut cost as much as possible and eliminate non promising candidates. Realistically if a molecule doesn't work in mice sure it could work in humans, but you'd be better off just doing the mouse study so you only need to run one trial instead of 10 and use the savings to invest in other trials.

Human trials are insanely expensive. One of my colleagues works at a company that pays well over $100k for a single primate for preclinical testing. Doing it in people is even more expensive with the massive costs of just organizing and insuring a trial. Comparatively it is very easy and cheap to inject a couple dozen mice with a drug and watch them for 6 months.

Also mixing trial candidates is a really bad idea, CYP liver enzyme reactions are a real thing and are often very different for humans and animals. Doing it with one drug is dangerous enough, but mixing 25 where one may inhibit decomposition of another is a recipie for dead people. You'd also need a very very large number of people (likely thousands) to deconvolute the statistical noise.

Well for the studios the art is the product. For researchers the ideas and data are the product and the writing is packaging. It's not a perfect analogy but it gets across why I personally don't get up in arms about this. Provided the findings aren't being changed does it really matter? Sometimes chatgpt is a useful editor for flow in the same way you'd ask a colleague or spouse.

And If it levels the playing field between native English speakers and foreigners that is good in my book.