Hair Loss: PP405 and the MPC Pathway
Research and education, not medical advice.
This page compiles my own posts on PP405 into one reference. It covers why I think PP405 is the most promising hair-loss approach, how we reverse-engineered the patents to model the real candidates, and the correction I had to make publicly when I realized JXL082 is not PP405.
Why PP405 is different
PP405 was chosen due to early clinical trial press releases that demonstrate growth in under a month, and specifically the drug’s action on stem cell activation rescuing hair in dormant, bald regions. This differs from AR-targeted drugs, which operate on the basis of AR-induced miniaturization, which cannot necessarily help in cases where it has been too late and the damage too severe.
Mitochondrial pyruvate carrier (MPC) inhibition
Hair growth is dictated by the activity of hair follicle stem cells, which can be stimulated by lactate dehydrogenase, which reduces pyruvate to lactate. Lactate dehydrogenase can be increased by MPC inhibition, which then leads to hair growth in preclinical (and clinical) models. This is where JXL-069 was shown to be an effective MPC inhibitor. [7]
The clinical signal
Pelage has publicly described exactly the profile for PP405:
- Phase 1, which showed daily topical dosing with no detectable drug in blood, and bulge-localized signals (Ki67, hair germs). [1]
- Phase 2a, which reported no systemic absorption detected in blood, and a striking exploratory signal: 31% of higher-hair-loss men had >20% density increase at Week 8 vs 0% placebo after only 4 weeks of dosing. [2]
- Clinical trials, which explicitly lists the intervention as PP405 0.05% topical gel, applied once daily. [3]
The challenge is to determine which formulation can effectively penetrate the scalp and activate the bulge without systemic exposure, using a 0.05% daily gel. To get bulge Ki67 without detectable blood, the compound has to enter the follicle, then convert locally into an active form that stays trapped in the tissue, which implies PP405 is engineered to do something very specific:
- Reach the follicle/bulge vicinity.
- Hand off into living tissue and convert locally into the active acid.
- Avoid the depot trap, where dose parks in SC/sebum long enough to be carried out or washed off before doing work.
The patent breakdown
Here are our findings for the PP405 project. Inspiration for listing 3HP Mono-CF3 and 2HEE is on behalf of Slymon, a patent researcher and friend from our community on discord. Information on these compounds are what he presented me as reasoning. Both Mono-CF3 3HP and PP30 have been listed, with 2HEE commissioned and being synthesized. Please note that while these are likely candidates of PP405, with available data it is impossible to say which is genuinely PP405. It is possible that some, if not all are mere analogs of PP405, despite our best efforts.
That being said, we have used liposome-based carrier gels that were evidenced to work in published literature and patents (first starting with PLO gel which was explicitly mentioned, then moving to TD Lipo Gel which is newer and supposed to be of similar function but superior). Note that other companies selling PP405 derivatives don’t say the actual name of their carrier, which is really important for topical drugs. Third party testing proved high purity on our PP405-related synthesis projects.
3HP Mono-CF3 vs 3,5-bis(CF3)
First it would be good to specifically go over our current version of the 3HP, which is 3HP Mono-CF3, and how it compares to the 3,5-bis(CF3) variant. Both still operate on the scaffold of JXL-069, which possesses the relevant mechanism of action (mitochondrial pyruvate carrier inhibition). Actual PP405 is not JXL-069, it is a prodrug which optimizes transdermal pharmacokinetics to deliver the compound and avoid blood accumulation.
Exact Structures (SMILES):
- Compound A (bis-CF3):
OCCCOC(=O)C(C#N)=Cc1cn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncccc12 - Compound B (mono-CF3):
OCCCOC(=O)C(C#N)=Cc1cn(Cc2cccc(C(F)(F)F)c2)c2ncccc12
RDKit-Computed Physicochemical Properties:
| Property | Compound A (bis-CF3) | Compound B (mono-CF3) |
|---|---|---|
| Molecular Weight (Da) | 497.395 | 429.398 |
| cLogP (Crippen) | 4.955 | 3.936 |
| ∆MW (B − A) (Da) | -67.997 | |
| ∆cLogP (B − A) | -1.019 |
Potts–Guy Permeability Model — log10(Kp) = 0.71·logP − 0.0061·MW − 6.3 (Kp in cm/s):
- Compound A: log10(Kp) = -5.816 → Kp ≈ 1.53e-06 cm/s
- Compound B: log10(Kp) = -6.125 → Kp ≈ 7.50e-07 cm/s
- Kp ratio (B/A) ≈ 0.491×
Solubility-Limited Flux Model — flux proxy Jmax ∝ Kp · S. Vehicle-matched aqueous solubility constraint from patent data: S_B / S_A > 20×. Therefore Jmax_B / Jmax_A ≈ (Kp_B/Kp_A) · (S_B/S_A) ≈ 0.491 · (S_B/S_A). If S_B/S_A = 20 → Jmax_B/Jmax_A ≈ 9.82×; if S_B/S_A = 40 → Jmax_B/Jmax_A ≈ 19.64×.
For this exact SMILES pair, Potts–Guy predicts the mono-CF3 prodrug has ~0.49× intrinsic permeability relative to the bis-CF3 prodrug. In a solubility-limited aqueous vehicle regime where S_B/S_A > 20×, the flux proxy Jmax ∝ Kp·S still favors the mono-CF3 architecture by >~9.8× before accounting for any activation yield (Y) or potency (IC50) differences.
Why we centered mono-CF₃
PP405 requires rapid entry, handoff, and local conversion, avoiding prolonged presence as an intact, neutral, lipid-seeking prodrug. Increasing CF₃ loading usually increases lipophilicity, which increases two failure modes that contradict PP405’s phenotype:
- Lipid parking: Higher partitioning into SC lipids and follicular sebum. Increased Lipid Parking = Storage unless Handoff and Conversion occur rapidly.
- Waste and leak window: Sebum flows outwards. Thus, a parked dose is subject to Carry-Out/Wash-Off; longer intact residence also increases the chance of systemic diffusion before conversion.
Mono-CF₃ keeps enough lipophilicity for entry while reducing depot pressure, shortening intact residence, and improving robustness across oily vs dry scalps.
Modeling and the candidate slate
Pelage’s patents list all promoiety classes. Before modeling, we penalized those classes that produce reactive byproducts or favor lipid parking and outflow loss. From here we ran all exemplified compounds through a series of models, where each model tracks where the applied dose goes over time across connected pools (gel, surface lipids, follicle sebum by depth, living tissue), then summarizes the run into three practical outputs: useful active acid created, dose stuck in depots, and dose lost before conversion.
- Model 0: Basic efficiency. How much dose becomes active acid in living tissue vs getting stuck or wasted.
- Model 1 (Head to Head): Adds depth bins (upper/deep/bulge) so “follicle loading” isn’t enough; bulge reach matters.
- Model 2: Adds higher enzyme activity near the surface; flags candidates that convert too early and trap shallow.
- Model 3: Adds sebum movement; time spent in sebum becomes a loss risk via outward flow.
- Model 4: Adds the deep-barrier possibility; a slightly more lipophilic candidate can win at bulge depth in that regime. In the deep-wall scenario the bulge ranking flips, which is why 3HP is carried as the hedge.
In all scenarios, the winners cluster into the same narrow slate. Within the mono CF₃, hydroxy-terminated set, the most defensible identity shortlist is: 2HEE, 2HE, and 3HP. 2HEE and 2HE have identical behavior as far as delivery phenotypes go, with 2HE acting as the closest backup/control compound to 2HEE. The two candidate leads that stand alone as distinct are 2HEE and 3HP. 2HEE is the preferred throughput lead, while 3HP is the “depth” hedge that becomes increasingly attractive as access to the bulge becomes more limited by barriers and slightly greater lipophilicity is advantageous at the level of the depth.
PP30
PP30 (1-Acetyloxyethyl (E)-3-(1-(3,5-bis(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyanoacrylate) is from a different patent, [6] wherein it is shown that the prodrug converts at an even distribution between prodrug and the active chemical, indicating that it doesn’t overpenetrate or lack the capacity to break down once in drug. This delivers the unmodified JXL-069, as described in literature.
This chart is useful because it shows the applied pharmacokinetics without having to use as many simulations to predict the effects. That being said, results with PP30 in people were mixed, meaning it was either a failure of those companies (due to purity, or the carrier used), or it’s simply a red herring. In any case, it does seem like, even if it wasn’t PP405, it should theoretically be active if the data is to be believed, as a prodrug delivering JXL-069.
Main conclusion
There are arguments to be made for the efficacy of 2-HEE, 3HP (both Mono-CF3 and 3,5-bis(CF3)), and PP30 and them being potentially being PP405. However, it won’t be confirmed until Pelage themselves reveal the structure. However, we will attempt to carry the suspected varieties until that day comes. In either case, given the lack of options, the excellent preclinical and clinical data of PP405 for treating prolonged baldness at the source, through stem cell activation, is quite promising. Again, final thanks to Slymon for his work in deciphering patents and making this possible.
The JXL082 correction
JXL082 is not the real PP405. It’s an analog. I’ve turned off sales for now so I can educate people of this slip-up, and I am going to synthesize the real one which means the actual PP405 is pushed back, and if you want to be refunded due to this, send an email. We will still make JXL082, but you need to understand it’s not PP405.
I guess Slymon didn’t read all the patents. And only just now realized his mistake, months later… Very unfortunate for the project. He even wrote this entire document about why it’s JXL082 which was pages long, but now he realizes that JXL082 was a step towards the development of PP405. Which means that JXL082, while it probably still works, is less efficient than the actual PP405. Long hydrolysis vs. fast hydrolysis to the compound JXL069. Still a topical prodrug, but not PP405. Really sorry about this. But I promise to make the right one now. And that shouldn’t take too long.
Is JXL the same “thing” as PP405 just less potent/bioavailable? Basically yes. Apparently, PP405 hydrolyzes about ~150%+ quicker. It only converted to JXL069 in dermal layers at a rate of 1-3%. Therefore, it doesn’t work much. No reference material sites sell actual PP405, which is why I was attempting to be the first.
The toxicity question
People said that it will “convert in the blood and become toxic”. That’s unlikely. The amount used, 0.05% isn’t enough to even do that significantly, but JXL082 is still going to mostly exert activity in the dermal layers. But less effectively than PP405.
To spell it out:
- IC50 isn’t going to relate to transporters in a way that causes toxicity. You can’t claim off targets due to an ineffective IC50.
- The amount concentration used is the same as PP405, which is minimal, and thus very little would enter the blood, as it was formulated for topical use specifically and targeting the dermal layers.
- Me and friends have already used it and not experienced toxicity. It’s less of a concern about toxicity, more a problem of impotency.
“Yes I can claim toxicity if IC50 isn’t low enough”, no, you quite literally can’t, it shows you don’t understand pharmacology at all because that just means impotency, which is quite literally expected because both JXL082 and PP405 are prodrugs to the active compound JXL069. And impotency does not translate to toxicity, you are now straight up lying about me, and my intentions. If I was really just after sales I wouldn’t have made this fucking post, which is literally signaling to my customers not to buy it if they wanted PP405. And you also fail to realize how miniscule the amount is used concentration wise for PP405; it’s miniscule because it’s potent. Systemic absorption is expected for both variants, but drug toxicity is concentration dependent. Let’s say hypothetically PP405 is toxic after it goes systemic, will to achieve systemic toxicity you’d need an amount relative to the cell volume. And that’s not achieved.
You are making a false dichotomy here saying that if it’s less potent then that activity is fulfilled by another target. That’s not true. Prodrugs are not meant to be active intrinsically, and yes it would be better to have more data, but that’s always the case. Actually there is cell viability testing on JXL082 I can link you to.
JXL082 is a prodrug to JXL069, and so is PP405. JXL069 is the active compound, it can’t be used effectively when it’s not in prodrug form. That is without a doubt false, PP405 is absolutely not JXL069 and anything else is misinformation.
The real PP405 synthesis is the goal
The actual PP405 is pushed back, but I promise to make the right one now. We need more options, and no reference material sites sell actual PP405, which is why I was attempting to be the first.
On competitors
We have been banned/blacklisted from r/tressless and I believe this may be due to their affiliation with Umbrella Labs, who is a pretty aggressive competitor to us and seem to really want to inhibit our growth.
Umbrella labs is run by people who just relist what they see other people selling and this is why. Lol.
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