Hubbry Logo
TalarozoleTalarozoleMain
Open search
Talarozole
Community hub
Talarozole
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Talarozole
Talarozole
Talarozole
View on Wikipedia
from Wikipedia
Talarozole
Clinical data
Routes of
administration		By mouth, topical
ATC code
  • none
Identifiers
  • N-(2-Benzothioazolyl)-N-[4-[2-ethyl-1-(1,2,4-triazo-1-yl)butyl]phenyl]amine
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H23N5S
Molar mass377.51 g·mol−1
3D model (JSmol)
  • c2ncnn2C(C(CC)CC)c(cc3)ccc3Nc4nc1ccccc1s4
  • InChI=1S/C21H23N5S/c1-3-15(4-2)20(26-14-22-13-23-26)16-9-11-17(12-10-16)24-21-25-18-7-5-6-8-19(18)27-21/h5-15,20H,3-4H2,1-2H3,(H,24,25) ☒N
  • Key:SNFYYXUGUBUECJ-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Talarozole (formerly R115866, planned trade name Rambazole) was an investigational drug for the treatment of acne, psoriasis and other keratinization disorders. Development for that purpose has been discontinued.[1] However, its effect in increasing retinoic acid is now being investigated in hand and knee osteoarthritis.[2]

Talarozole inhibits the metabolism of retinoic acid by blocking cytochrome P450 enzyme CYP26 isoenzymes (CYP26A1 and possibly also CYP26B1), retinoic acid hydroxylases.[3] Because of this mechanism, it is called a retinoic acid metabolism blocking agent (RAMBA).[3][4]

It has 750-fold higher potency than the earlier drug liarozole as well as greater selectivity, with more than 300-fold selectivity for inhibition of CYP26A1 over other steroid-metabolizing enzymes like CYP17A1 (17α-hydroxylase/17,20-lyase) and aromatase (CYP19A1).[3][5]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Talarozole

View on Grokipedia
from Grokipedia
Talarozole (previously known as R115866) is an investigational small-molecule drug that acts as a selective metabolism-blocking agent (RAMBA) by inhibiting the CYP26A1, thereby preventing the of all-trans and elevating its endogenous levels in tissues such as the skin and joints. This mechanism enhances signaling, which normalizes epidermal differentiation and reduces inflammation in keratinization disorders. Originally developed by Barrier Therapeutics (later acquired by ), talarozole underwent phase II clinical trials for moderate to severe plaque-type , demonstrating significant reductions in (PASI) scores with oral doses of 1 mg daily over 8 weeks, though development for dermatological indications was discontinued around 2009 due to limited advancement beyond phase II. More recently, talarozole has been repurposed for osteoarthritis (OA), particularly hand OA, based on genetic associations linking variants in the ALDH1A2 gene—which encodes a retinoic acid-synthesizing enzyme—to increased OA risk in large cohort studies from Iceland and the UK. Preclinical studies in mouse models of post-traumatic OA, such as destabilization of the medial meniscus (DMM), have shown that systemic administration of talarozole (via minipumps delivering doses in PEG 300/DMSO) suppresses mechanoinflammation by downregulating pro-inflammatory genes like Il1b, Il6, Adamts4, Mmp3, and Ccl2 within 6 hours post-injury, while also attenuating cartilage degeneration, osteophyte formation, and joint damage over 4 weeks. Ex vivo experiments on injured porcine cartilage further confirmed reduced inflammatory responses, suggesting talarozole's potential as a disease-modifying agent that modulates retinoic acid via PPARγ pathways to counteract OA progression. As of November 2025, no human trials for OA have been completed, though a phase II proof-of-concept trial (RAMBOH-1) investigating its effects on gene expression in hand osteoarthritis is ongoing, with recruitment as of August 2025. Its established safety profile from prior dermatology studies positions it as a candidate for future clinical evaluation in this common condition affecting approximately one in three adults over the age of 65.

Chemical properties

Molecular structure

Talarozole is a synthetic organic compound classified as a retinoic acid metabolism-blocking agent (RAMBA). Its IUPAC name is N-[4-[(1R)-2-ethyl-1-(1,2,4-triazol-1-yl)butyl]phenyl]-1,3-benzothiazol-2-amine. The molecular formula of talarozole is C21H23N5S, with a molar mass of 377.51 g/mol and CAS number 870093-23-5. Structurally, it features a benzothiazole core—a fused benzene and thiazole ring system—linked via a secondary amine to a para-substituted phenyl ring. This phenyl ring is attached to a chiral butyl chain bearing an ethyl substituent at the 2-position and a 1,2,4-triazol-1-yl group at the 1-position, with the (R)-configuration at the chiral center. The SMILES notation for talarozole is CCC(CC)C(c1ccc(Nc2nc3ccccc3s2)cc1)n1cncn1. Previously, the compound was identified as R115866 during its development, with the planned Rambazole.

Physical and chemical characteristics

Talarozole appears as a to off-white . It exhibits poor in , with a reported value of 0.0145 mg/mL, but demonstrates good in organic solvents, including greater than 50 mg/mL in DMSO and at least 9.34 mg/mL in . The compound's (LogP) is predicted to be 5.9, reflecting its lipophilic nature, which supports its use in both topical and oral formulations. Talarozole, with the molecular formula C21_{21}H23_{23}N5_5S and a molecular weight of 377.51 g/mol, maintains stability under recommended storage conditions of -20°C in a dark, dry, sealed environment to prevent degradation from light and oxidation. Talarozole was synthesized as a third-generation derivative via multi-step organic processes, including N-alkylation reactions to attach the 1,2,4-triazole group to a phenyl-substituted intermediate and formation of the benzothiazol-2-amine moiety, as detailed in WO1997049704A1 filed by Janssen Pharmaceutica N.V. (a subsidiary) in 1997.

Pharmacology

Mechanism of action

Talarozole is a selective inhibitor of the enzymes CYP26A1 and CYP26B1, which are primarily responsible for the catabolism of all-trans (atRA) through 4-hydroxylation. By potently blocking this , talarozole prevents the conversion of atRA to inactive metabolites such as 4-hydroxy-atRA and 4-oxo-atRA. The compound exhibits IC50 values in the range of 4-5 nM for CYP26A1 and approximately 40 nM for CYP26B1 in recombinant enzyme assays. This inhibition leads to elevated intracellular and systemic levels of endogenous atRA, with preclinical models showing increases of up to 5.7-fold in serum and 1.5- to 4-fold in tissues such as , liver, and following oral dosing. The accumulation of atRA subsequently enhances signaling by increasing ligand availability for retinoic acid receptors (RARs) and retinoid X receptors (RXRs), without talarozole directly binding or agonizing these nuclear receptors. These downstream effects include promotion of epidermal differentiation (e.g., upregulation of involucrin and HB-EGF expression), reduction of hyperproliferation (e.g., decreased 10 levels), and modulation of inflammatory responses (e.g., lowered IL-1 expression in ). Talarozole demonstrates high selectivity for the CYP26 family, with over 300-fold higher IC50 values for other enzymes such as , CYP19, CYP17, and CYP2C11 (typically in the micromolar range, e.g., IC50 >3 μM for ). This profile minimizes off-target effects on broader metabolism while specifically amplifying endogenous activity.

Pharmacokinetics

Talarozole can be administered via oral and topical routes, with the oral formulation providing systemic exposure and the topical formulation targeting local skin delivery. Following oral administration, talarozole exhibits rapid absorption, achieving peak plasma concentrations (Cmax of approximately 20.7 ng equiv/mL) at around 3 hours (Tmax) in humans, based on a radiolabeled study. Preclinical data in mice indicate even faster absorption, with Tmax at 0.5 hours after a 2.5 mg/kg dose, and an estimated bioavailability approaching 100% when formulated in PEG 300. Topical application results in limited systemic absorption, with estimated plasma concentrations below 2 nM, while achieving high local concentrations in the skin (up to 1.59 × 105 nM in the epidermis after application of a 0.3% gel). As a highly lipophilic compound (logP ≈ 5.9), talarozole preferentially distributes to lipid-rich tissues such as and liver. In topical applications, approximately 80% remains in the and 20% in the , with up to 275 μm after 12 hours. Systemic distribution shows accumulation in these organs, though specific volume of distribution values are not well-documented; preclinical models suggest moderate distribution without significant blood-brain barrier penetration. Talarozole undergoes extensive hepatic primarily via CYP3A4-mediated oxidation, including ring and modifications, leading to multiple metabolites such as oxidized forms and glucuronides. Major circulating metabolites account for up to 27.8% of plasma AUC in s, with no evidence of auto-induction. Elimination occurs mainly through fecal excretion (72% in humans), with minor urinary elimination (7%), consistent with extensive and biliary clearance. The terminal is approximately 19.4 hours in human males following oral dosing, while preclinical data report a shorter 2.2 hours; topical in is estimated at 4-6 hours based on diffusion profiles. No significant accumulation occurs with multiple dosing. By inhibiting CYP26 enzymes, talarozole elevates endogenous all-trans- (atRA) levels; in preclinical models, oral doses (e.g., 2.5 mg/kg) increase baseline serum atRA from approximately 0.3 ng/mL (1 nM) up to about 1.7 ng/mL (5.7 nM) without significant tissue accumulation beyond serum upon multiple dosing.

Therapeutic applications

Dermatological disorders

Talarozole has been investigated primarily for dermatological disorders involving abnormal epidermal keratinization and hyperproliferation, such as plaque-type , vulgaris, and congenital ichthyoses like recessive . By selectively inhibiting 26 enzymes, talarozole elevates endogenous all-trans (atRA) levels in the skin, which helps normalize epidermal differentiation, alleviate scaling, and suppress hyperproliferation in preclinical models of . In plaque-type psoriasis, an open-label pilot trial involving 19 patients with moderate to severe disease evaluated oral talarozole at 1 mg daily for 8 weeks, resulting in a significant reduction in (PASI) scores from baseline, with 26% of participants achieving at least a 50% improvement (PASI50) at the end of treatment and 47% at 2-week follow-up. Subsequent phase 2 dose-ranging studies (NCT00716144) assessed higher oral doses up to 5 mg over 12 weeks in larger cohorts, but detailed published results remain unavailable. An additional open-label phase 2 trial (NCT00725348) in moderate to severe plaque further confirmed tolerability and preliminary efficacy with . For acne vulgaris, phase 2 trials explored both oral and topical formulations. An open-label phase 2 study (NCT00725439) of oral talarozole in facial assessed and over 12 weeks, but results have not been publicly reported. A phase I trial of topical talarozole (1% concentration) assessed local with minimal systemic exposure. Talarozole received European designation in 2012 for recessive , a hyperkeratinization disorder, which was later withdrawn, based on its potential to enhance atRA-mediated barrier normalization and reduce scaling through preclinical and early data. Available formulations include oral capsules for systemic treatment of widespread conditions like and topical gels for localized applications such as , allowing targeted delivery to affected areas. Despite evidence of efficacy across these trials, development was suspended in by Barrier Therapeutics (later acquired by Stiefel/GSK) as part of cost-cutting measures, resulting in no approved indications to date.

Osteoarthritis

Talarozole is emerging as a potential repurposed therapy for hand , encompassing both post-traumatic and idiopathic subtypes, with preclinical models suggesting applicability to as well. The therapeutic rationale centers on its capacity to suppress mechanoinflammation in articular joints by elevating endogenous levels of all-trans (atRA), which in turn downregulates key inflammatory genes such as IL-6 and MMP13 in chondrocytes. This approach addresses the role of atRA deficiency, linked to genetic variants in ALDH1A2 that predispose individuals to severe hand . Preclinical evidence from mouse models of post-traumatic supports talarozole's disease-modifying potential. In the destabilization of the (DMM) model, talarozole administration rapidly suppressed mechanoinflammatory in knee within 6 hours post-injury, including reductions in IL-6, IL-1β, ADAMTS4, , and CCL2. Longer-term studies showed it attenuated OA progression, with decreased degradation and formation observed after 26 days or 4 weeks post-surgery. experiments in injured pig further confirmed its anti-inflammatory effects on chondrocytes. Human translation is under investigation through the ongoing RAMBOH-1 proof-of-concept study, recruiting patients with symptomatic hand at the base of the thumb . Participants receive 2 mg oral talarozole daily for 14 days prior to , with assessments focusing on (e.g., ADAMTS4, MMP13, MMP1), markers, via numeric rating scale, function via patient evaluation measure, and via EQ-5D-5L. The trial, initiated in 2020 and expected to conclude in December 2025, aims to validate molecular and symptomatic improvements. Compared to direct therapies, talarozole exhibits lower toxicity by selectively inhibiting CYP26 enzymes to enhance endogenous atRA signaling rather than exogenous administration. Its favorable safety profile is supported by prior phase II trials in , where doses up to 5 mg daily were well-tolerated with minimal adverse effects. This positions it as a promising candidate for chronic conditions requiring sustained treatment.

Development and research

History

Talarozole was synthesized in the mid-1990s by researchers at Janssen Pharmaceutica N.V., a of , as part of efforts to develop azole-based retinoic acid metabolism blocking agents (RAMBAs) targeting enzymes involved in all-trans . The compound, initially designated R115866, was patented in 1997 under World Intellectual Property Organization publication WO 1997049704. In 2002, licensed talarozole to Barrier Therapeutics Inc. for dermatological applications, focusing on its potential to elevate endogenous levels in the skin. Barrier Therapeutics advanced the compound through early clinical evaluation, completing Phase I trials by 2005 that demonstrated a favorable safety profile in healthy volunteers, with minimal systemic absorption when applied topically. Corporate milestones followed in quick succession: Barrier Therapeutics was acquired by in August 2008 for approximately $148 million, integrating talarozole into Stiefel's dermatology portfolio. Stiefel itself was then purchased by GlaxoSmithKline (GSK) in July 2009 for $2.9 billion, positioning talarozole within GSK's global research and development framework. Development for dermatological indications was halted by Barrier Therapeutics in 2008, despite encouraging Phase II results showing efficacy in , primarily due to strategic reprioritization and cost-cutting measures. Interest in talarozole resurfaced around 2020, when researchers at the and collaborators began investigating its repurposing for , capitalizing on the established safety data from prior studies to explore its anti-inflammatory effects via modulation in joint tissues.

Clinical trials

Talarozole underwent phase 2 clinical evaluation for dermatological indications, including psoriasis and acne, primarily between 2007 and 2010. A randomized, evaluator-blind, placebo-controlled dose-ranging study involving 176 patients with moderate to severe plaque psoriasis tested oral doses of 0.5 mg, 1 mg, or 2 mg daily for 12 weeks, demonstrating PASI-75 responses of 18.4%, 29.4%, and 37.1% respectively, compared to 7.1% for placebo. An open-label trial (NCT00725348) evaluated oral talarozole in patients with moderate to severe plaque psoriasis. For acne, an open-label phase 2 trial (NCT00725439) assessed 1 mg oral daily in 17 patients with moderate to severe facial acne for 12 weeks, achieving a 76% reduction in total lesion count from baseline. These studies confirmed talarozole's efficacy in improving skin lesions and psoriasis severity, with plasma all-trans retinoic acid levels elevated up to 2-fold. The safety profile across dermatology trials was favorable, with primarily mild to moderate adverse events such as dry skin (reported in up to 25% of participants), , (approximately 10%), and pruritus; no serious retinoid-like toxicities, such as , were observed. As a retinoic acid metabolism-blocking agent, talarozole carries teratogenic risks similar to systemic retinoids and is contraindicated in or for women of childbearing potential without effective contraception. The development program was suspended in 2008 by Barrier Therapeutics due to strategic priorities, with no phase 3 trials initiated and no filed. In , talarozole is under investigation in a phase 2 proof-of-concept trial (ISRCTN16717773), a double-blind, randomized, -controlled study enrolling 56 patients with hand at the base of the thumb. Participants receive 2 mg oral talarozole daily for 14 days prior to , with the primary endpoint assessing differences in inflammatory gene mRNA expression (e.g., ADAMTS4, MMP13) at compared to . The trial, which began in 2020, remains ongoing as of November 2025, with an anticipated completion by December 31, 2025; early preclinical and mechanistic data indicate elevation of all-trans in joint tissues without dermatological side effects. Overall, talarozole holds status, with research focused on in early clinical stages and no completed phase 3 trials across indications.

References

  1. https://go.drugbank.com/drugs/DB13083
  2. https://pubmed.ncbi.nlm.nih.gov/18951302/
  3. https://clinicaltrials.gov/study/NCT00725348
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC10823836/
  5. https://www.oarsijournal.com/article/S1063-4584(22)00120-0/fulltext
  6. https://www.isrctn.com/ISRCTN16717773
  7. https://pubmed.ncbi.nlm.nih.gov/35410675/
  8. https://www.chemspider.com/Chemical-Structure.7975653.html
  9. https://pubchem.ncbi.nlm.nih.gov/compound/Talarozole
  10. https://www.biosynth.com/p/BIA41053/201410-53-9-talarozole
  11. https://pubchem.ncbi.nlm.nih.gov/compound/44421596
  12. https://pubchem.ncbi.nlm.nih.gov/compound/R_-Talarozole
  13. https://www.caymanchem.com/product/42372/talarozole
  14. https://www.chemicalbook.com/ChemicalProductProperty_EN_CB52628344.htm
  15. https://www.apexbt.com/talarozole.html
  16. https://patents.google.com/patent/WO1997049704A1/en
  17. https://pmc.ncbi.nlm.nih.gov/articles/PMC4366427/
  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC5469401/
  19. https://pubmed.ncbi.nlm.nih.gov/21228620/
  20. https://patents.google.com/patent/US8188124B2/en
  21. https://www.researchgate.net/publication/49749304_Local_Skin_Pharmacokinetics_of_Talarozole_a_New_Retinoic_Acid_Metabolism-Blocking_Agent
  22. https://pmc.ncbi.nlm.nih.gov/articles/PMC7329915/
  23. https://www.orpha.net/en/drug/substance/300642
  24. https://pubmed.ncbi.nlm.nih.gov/17714122/
  25. https://clinicaltrials.gov/study/NCT00725439
  26. https://gsrs.ncats.nih.gov/ginas/app/ui/substances/XKD9N5CJ6W
  27. https://www.science.org/doi/10.1126/scitranslmed.abm4054
  28. https://www.ndorms.ox.ac.uk/news/new-drug-offers-hope-for-people-with-hand-osteoarthritis
  29. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2133.2008.08895.x
  30. https://www.biospace.com/stiefel-laboratories-completes-acquisition-of-barrier-therapeutics-inc
  31. https://www.gsk.com/en-gb/media/press-releases/glaxosmithkline-completes-acquisition-of-stiefel/
  32. https://adisinsight.springer.com/drugs/800020802
  33. https://gtr.ukri.org/projects?ref=MR%2FS035664%2F1
  34. https://www.isrctn.com/pdf/16717773
Add your contribution
Related Hubs
User Avatar
No comments yet.