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ACP-105 (ACP105; ACP 105) is a novel, nonsteroidal and orally bioactive SARM (selective androgen receptor modulator) that has been investigated for the treatment of age-related cognitive decline. It activates AR wild type and AR mutatant T877A with pEC50 of 9.0 and 9.4, respectively.
| Targets |
Androgen receptor (AR) – pEC₅₀ = 9.0 ± 0.3, efficacy = 81 ± 6% (relative to DHT), pKᵢ = 9.4 ± 0.3 (R-SAT functional cell-based assay) [1]
AR mutant T877A – efficacy = 37 ± 5%, pKᵢ = 5.5 ± 0.4 (no pEC₅₀ value reported) [1] |
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| ln Vitro |
The selective androgen receptor modulator (SARM) ACP-105 is available for oral administration. Its pEC50 values for the AR wild type and T877A mutant are 9.0 and 9.3, respectively. In human hepatocytes, ACP-105 (Compound 1) has a half-life of 5.0 hours [1].
ACP-105 acted as a partial agonist at the wild-type androgen receptor in R-SAT assays, with a pEC₅₀ of 9.0 ± 0.3 and 81 ± 6% efficacy relative to dihydrotestosterone (DHT). In radioligand binding assays, it exhibited a pKᵢ of 9.4 ± 0.3 at AR. [1] In an AR transcriptional activity luciferase reporter gene assay, ACP-105 showed a pEC₅₀ of 9.6 ± 0.1 and efficacy of 86 ± 11%. [1] ACP-105 was evaluated in a panel of 47 other nuclear receptors and 31 selected G-protein-coupled receptors; no agonism or significant binding affinity was observed, indicating high selectivity. [1] |
| ln Vivo |
In both irradiated and sham-irradiated mice, ACP-105 increased cryogenic capacity (effect of ACP-105: F=5.44; p=0.028). There was a brain region × ACP-105 interaction for MAP-2 immunoreactivity in the cortex of sham-irradiated mice (F=6.655; p=0.0027). There is a tendency toward higher MAP-2 immunoreactivity in the entorhinal cortex, despite the fact that ACP-105 reduces MAP-2 immunoreactivity in the sensorimotor cortex [2].
In castrated male rats (orchidectomized, ORX), ACP-105 was delivered via subcutaneous osmotic pumps at doses of 0.1, 0.3, 1, and 3 mg/kg/day for 14 days. Testosterone propionate was administered at 0.75 mg/kg/day as a comparator. ACP-105 produced a robust anabolic effect on the levator ani muscle, with 67% reversal of ORX-induced atrophy at 1 mg/kg/day, while having lesser androgenic effects on the ventral prostate (21% reversal at the same dose; testosterone propionate reversed prostate atrophy by 48%). [1] To test whether ACP-105 acts as a partial agonist in vivo, ORX rats were dosed daily with testosterone propionate (1 mg/kg sc) alone or together with ACP-105 (10 mg/kg po) for 14 days. The androgenic effects of testosterone propionate on the prostate were attenuated by co-administration of ACP-105. [1] |
| Cell Assay |
R-SAT (receptor selection and amplification technology) functional cell-based assay: Mouse NIH-3T3 fibroblasts were plated in 96-well plates in DMEM with 10% calf serum and grown to 60-70% confluency. Transient transfections were performed using Polyfect, with expression vectors encoding the androgen receptor (200 ng), β-galactosidase (500 ng), and coactivators SRC1, DRIP205, and GRIP1 (10 ng each). Sixteen hours after transfection, cells were incubated with different concentrations of ligand in DMEM containing 30% ultrastructure and 0.4% calf serum to generate dose-response curves. After 5 days, plates were developed by adding a solution containing the β-galactosidase substrate o-nitrophenyl β-galactose (ONPG) in phosphate-buffered saline with 5% Nonidet P-40 detergent. Plates were read at 420 nm. Data were fit to the equation r = A + Bx/(x + c) to determine pEC₅₀ and efficacy. [1]
Luciferase reporter gene assay: AR transcriptional activity was measured using a luciferase reporter. For ACP-105, pEC₅₀ = 9.6 ± 0.1, efficacy = 86 ± 11% (values from Supporting Information referenced but not detailed in main text). [1] |
| Animal Protocol |
Castrated male rats (orchidectomized, ORX) were used to assess anabolic and androgenic activities. ACP-105 was delivered via subcutaneous osmotic pumps at doses of 0.1, 0.3, 1, and 3 mg/kg/day for 14 days. Testosterone propionate was administered at 0.75 mg/kg/day as a comparator. After 2 weeks of dosing, levator ani muscle and ventral prostate tissues were weighed and compared to sham-operated vehicle-treated controls. [1]
For the antagonism study, ORX rats were dosed daily with either testosterone propionate (1 mg/kg sc) alone or together with ACP-105 (10 mg/kg po) for 14 days. Twenty-four hours after the last dose, animals were sacrificed and prostate weights measured. [1] |
| ADME/Pharmacokinetics |
ACP-105 showed high oral bioavailability: in rats, F_oral = 38%; in dogs, F_oral = 56%. [1]
The half-life of ACP-105 in human hepatocytes was 5.0 hours. [1] Intrinsic clearance (Cl_int) in human liver microsomes was 287 μL/(mL·mg), and in rat liver microsomes 227 μL/(mL·mg) (values from Table 1; units as reported in the table). [1] |
| References |
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| Additional Infomation |
ACP-105 is a partial agonist of the androgen receptor, which may result in tissue-selective actions due to differences in receptor reserve content. In tissues with high natural androgen content (e.g., prostate), a partial AR agonist could act as a functional antagonist by competing with endogenous androgens. This was demonstrated in vivo where ACP-105 attenuated testosterone propionate-induced prostate growth. [1]
The compound was derived from SAR studies on tropanol derivatives. Key structural features include a 2-chloro-3-methylbenzonitrile aromatic moiety and a tropane ring with an endo-3-exo-methyl-3-hydroxy substitution. [1] ACP-105 is intended for potential clinical applications in diseases where anabolic effects are desired with minimal androgenic side effects, such as muscle wasting, osteoporosis, and male hypogonadism. [1] |
| Molecular Formula |
C16H19CLN2O
|
|---|---|
| Molecular Weight |
290.787863016129
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| Exact Mass |
290.118
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| CAS # |
899821-23-9
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| PubChem CID |
11638442
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
20
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| Complexity |
417
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CC1C(Cl)=C(C#N)C=CC=1N1[C@@H]2C[C@](C[C@H]1CC2)(O)C
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| InChi Key |
OUEODVPKPRQETQ-CHWSQXEVSA-N
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| InChi Code |
InChI=1S/C16H19ClN2O/c1-10-14(6-3-11(9-18)15(10)17)19-12-4-5-13(19)8-16(2,20)7-12/h3,6,12-13,20H,4-5,7-8H2,1-2H3/t12-,13-/m1/s1
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| Chemical Name |
2-Chloro-4-[(1R,5R)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octan-8-yl]-3-methylbenzonitrile
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| Synonyms |
ACP 105 ACP-105ACP105
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO : ≥ 103 mg/mL (~354.21 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4389 mL | 17.1945 mL | 34.3891 mL | |
| 5 mM | 0.6878 mL | 3.4389 mL | 6.8778 mL | |
| 10 mM | 0.3439 mL | 1.7195 mL | 3.4389 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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