Pyrimethamine
Diaminopyrimidines · given by oral · on the market since 2020
What it's made of
Each functional group on the molecule does a specific, predictable job.
Aromatic halogen
What it does. Slows liver breakdown and increases membrane crossing. Also fills space in a binding pocket, which often raises potency several-fold.
What it opens up. Better tissue penetration and longer duration, at the cost of higher fat storage.
Where it can get to
Predicted from molecular weight, lipophilicity, polar surface area and hydrogen-bond donor count. A drug can only act where it distributes, so this constrains which conditions are addressable before any biology is considered. derived
What it binds — and whether we can reach it · 3 of 7 reachable
Binding affinity is only meaningful against the plasma concentration reached at the approved dose. A target requiring higher concentrations cannot be engaged in a patient, whatever the in vitro potency. Most repurposing hypotheses fail at this step, and it is rarely checked before a trial is proposed. measured
| Target | Kind | Action | Affinity (pAct) | Can it be engaged? |
|---|---|---|---|---|
| CHRM1 | GPCR | — | 8.72 | Engaged easily |
| DHFR | Enzyme | — | 8.1 | Engaged easily |
| SLC47A1 | Transporter | inhibitor | 7.1 | Engaged |
| HEXA | Enzyme | — | 5.51 | Out of reach |
| HEXB | Enzyme | — | 5.35 | Out of reach |
| SLC22A1 | Transporter | — | 4.87 | Not reachable |
| CYP2C9 | Enzyme | — | 4.29 | Not reachable |
This molecule concentrates in urine. Local concentration therefore exceeds plasma, so targets that look unreachable on a plasma reading may still be engaged. assumed
Cytotoxic. Targets core cell-division machinery. Use is limited to conditions severe enough to justify that toxicity; risk-benefit inverts in chronic benign disease.
New uses, and who is already trying them
One card per candidate indication: the reasoning link by link, the evidence tier that governs how strongly it can be stated, and any registered trials.
5 of the 113 conditions linked to this drug’s targets have been checked against trial records so far. The rest are not ruled out — they are unchecked.
Tay-Sachs disease
Animal models onlyIt reduces disease in animal models; untested in humans.
Sandhoff disease
Animal models onlyIt reduces disease in animal models; untested in humans.
constitutional megaloblastic anemia with severe neur
Wide openIt acts on a target linked to this disease; untested, and the direction of effect is unverified.
Parkinson disease
Wide openIt acts on a target linked to this disease; untested, and the direction of effect is unverified.
rheumatoid arthritis
Wide openIt acts on a target linked to this disease; untested, and the direction of effect is unverified.
Why nobody will fund it
3 companies make this across 3 approved products. With that many manufacturers the price has fallen to production cost. A company funding a trial could not recover it — competitors could market the same molecule for the new indication immediately, without contributing.
A new route or dosage form qualifies for a 505(b)(2) application, which carries three years of exclusivity for that formulation. It is the only remaining route to exclusivity on a generic molecule.
What it would cost to find out
Derived, not quoted. Events needed is 4(zα+zβ)²/ln(HR)²; enrolment is that divided by the event rate and follow-up. The 1/ln(HR)² term dominates: halving the detectable effect size roughly quadruples enrolment. derived
Cost per person reached is the relevant metric for a non-commercial funder, since there is no revenue to set against the outlay.
Ask for ideas nobody has listed
Reasons from the functional groups and distribution above, excluding conditions already listed. Output is hypotheses for falsification, not findings. Not medical advice.
Who might pay for the trial
Trials of off-patent drugs are rarely funded by venture capital or pharma. They are paid for by government grants and disease foundations. Here is who has funded work on this molecule before, what federal mechanisms are open now, and which foundations fund trials in the disease areas it touches. measured
Open notices with an explicit mandate to fund work on approved or off-patent molecules.
Grants.gov lists US federal money. Many off-patent drug trials are supported by disease foundations and nonprofits. These are matched to the body systems this drug touches. assumed
Who manufactures it
Companies holding an approved abbreviated application for this molecule in the United States, from the FDA Orange Book. Supply already exists at scale, so a trial would not need a manufacturing programme — but any of these could also be a partner, or an objector.
Nothing on this page is medical advice. Candidate uses are unproven hypotheses derived from public data; established uses are listed for verification only. Figures carry their provenance inline — anything marked assumed or derived is not a measurement.
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