Acoltremon (WS-12; AR-15512) is a potent and specific TRPM8 agonist, an analogue of menthol that works as a coolant. WS-12 displays analgesic effects and may be utilized in study/research of chronic neuropathic pain.
On May 29, 2025, The FDA approved acoltremon ophthalmic solution (Tryptyr, formerly AR-15512) 0.003% for the treatment of dry eye disease (DED). The new approval is for a first-in-class TRPM8 receptor agonist to stimulate corneal sensory nerves to increase natural tear production.

Physicochemical Properties

Molecular Formula	C18H27NO2
Molecular Weight	289.419
Exact Mass	289.204
Elemental Analysis	C, 74.70; H, 9.40; N, 4.84; O, 11.06
CAS #	68489-09-8
PubChem CID	11266244
Appearance	White to off-white solid powder
LogP	4.415
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	2
Rotatable Bond Count	4
Heavy Atom Count	21
Complexity	334
Defined Atom Stereocenter Count	3
SMILES	C[C@@H]1CC[C@H]([C@@H](C1)C(=O)NC2=CC=C(C=C2)OC)C(C)C
InChi Key	HNSGVPAAXJJOPQ-XOKHGSTOSA-N
InChi Code	InChI=1S/C18H27NO2/c1-12(2)16-10-5-13(3)11-17(16)18(20)19-14-6-8-15(21-4)9-7-14/h6-9,12-13,16-17H,5,10-11H2,1-4H3,(H,19,20)/t13-,16+,17-/m1/s1
Chemical Name	(1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-propan-2-ylcyclohexane-1-carboxamide
Synonyms	WS12; WS-12; (1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(propan-2-yl)cyclohexane-1-carboxamide; Fema No. 4681; ...; Acoltremon; WS 12
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	TRPM8
ln Vitro	In tests involving heterologously produced TRP ion channels, Acoltremon (10 μM) exhibits TRPM8 agonism [1]. In DRG neurons, acoltremon (1 or 10 μM; 0-250 s) seems to be a very strong and selective TRPM8 channel agonist [1].
ln Vivo	In mice, acoltremon (ip; 10 mg/kg; once) produces analgesic effects by activating TRPM8 specifically [1].
Cell Assay	Cell Viability Assay[1] Cell Types: HEK293T Cell Tested Concentrations: 10 μM Incubation Duration: Experimental Results: Activates mouse TRPM8 (mTRPM8), but neither activates nor inhibits mTRPA1. Cell viability assay[1] Cell Types: Cultured Mouse DRG Neurons Tested Concentrations: 1 or 10 μM Incubation Duration: 0-250 s Experimental Results: Approximately 10% to 14% of cultured wild-type neurons were shown to respond to WS-12 .
Animal Protocol	Animal/Disease Models: Trpm8–/– mice and capsaicin-injected mice [1] Doses: 10 mg/kg Route of Administration: intraperitoneal (ip) injection; 10 mg/kg; primary Experimental Results:significant analgesic effect in Trpm8-/ -The effect is lost in mice. In the rotarod test, mice demonstrated no change in latency decline. Reducing capsaicin-induced nociceptive behavior.
Toxicity/Toxicokinetics	(1R,2S,5R)-N-(4-Methoxyphenyl)-5-methyl-2-(1-methylethyl)-cyclohexanecarboxamide 2147 Scientific Opinion on Flavouring Group Evaluation 304 (FGE.304): Five carboxamides from chemical group 30 Commission Regulation (EC) No 1565/2000 (Repealed by Com. Implementing Reg. (EU) No 872/2012) doi:10.2903/j.efsa.2012.2903 2012-10-12 (1R,2S,5R)-N-(4-Methoxyphenyl)-5-methyl-2-(1-methylethyl)-cyclohexanecarboxamide 2524 Scientific Opinion on Flavouring Group Evaluation 304, Revision 1 (FGE.304Rev1): Four carboxamides from Chemical Groups 30 Commission Regulation (EC) No 1565/2000 (Repealed by Com. Implementing Reg. (EU) No 872/2012) doi:10.2903/j.efsa.2014.3769 2014-07-22
References	[1]. Prospects for prostate cancer imaging and therapy using high-affinity TRPM8 activators. Cell Calcium. 2007 Mar;41(3):285-94. [2]. Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels. Pak J Pharm Sci. 2008 Oct;21(4):370-8.
Additional Infomation	Acoltremon is under investigation in clinical trial NCT05493111 (A Long-term Safety Study Evaluating the Safety and Systemic Exposure of AR-15512). In pivotal Phase 3 trials, TRYPTYR demonstrated rapid natural tear production as early as Day 1 TRYPTYR is a first-in-class TRPM8 receptor agonist that rapidly stimulates natural tear production in patients with Dry Eye Disease (DED) Approximately 38 million individuals in the U.S. are living with DED, yet less than 10% of diagnosed patients are being treated with a prescription product

Solubility Data

Solubility (In Vitro)

DMSO : ~20 mg/mL (~69.11 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2 mg/mL (6.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	3.4552 mL	17.2759 mL	34.5519 mL
	5 mM	0.6910 mL	3.4552 mL	6.9104 mL
	10 mM	0.3455 mL	1.7276 mL	3.4552 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.