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| Targets |
PF-00446687 targets the melanocortin-4 receptor (MC4R), a G protein-coupled receptor involved in the regulation of energy homeostasis, sexual function, and other physiological processes. It acts as a potent and selective agonist at MC4R, with an EC50 of 12 +/- 1 nM. The compound is brain-penetrant and selectively activates adenylyl cyclase in cells expressing MC4R over those expressing MC1R, MC3R, or MC5R. PF-00446687 has also been reported to be a selective JAK3 inhibitor that suppresses the JAK/STAT signaling pathway.
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| ln Vitro |
MC4 absorption is bound by PF-00446687, which has a Ki of 27±4 nM. PF-00446687 exhibits very low efficacy against MC1, MC3, and MC5 uptake, as seen by its respective EC50 values of 1.02±0.30 μM, 1.16±0.35 μM, and 1.98±0.20 μM. The CEREP Bioprint Broad Ligand Screening Panel assessed PF-00446687's extensive off-target profile and found that the compound had the strongest binding activity at muscarinic M2 uptake (Ki=730 nM), sodium channels (Ki=690 nM), and sigma receptors (Ki=330 nM) [1].
In vitro studies have characterized PF-00446687 as a potent and selective MC4R agonist. It has an EC50 of 12 +/- 1 nM for MC4R. The compound selectively activates adenylyl cyclase in HEK293 cells expressing MC4R (EC50 = 0.012 uM) over cells expressing MC1R (EC50 = 1.02 uM), MC3R (EC50 = 1.16 uM), or MC5R (EC50 = 1.98 uM). Its potency and selectivity have been confirmed in multiple cell-based assays. The compound's activity at MC4R makes it a valuable tool for studying MC4R biology. |
| ln Vivo |
Internally reaching the brain, Pf-446687 is stable and has great selectivity for MC4R. In prairie voles, but not in non-monogamous meadow voles, peripheral injection of the highly selective small molecule MC4R agonist Pf-446687 and the brain-penetrating MC3/4R receptor peptide agonist Melanotan II (MTII) can accelerate the establishment of dietary preferences. It is devoid of any [2].
In vivo, PF-00446687 has been investigated for the treatment of erectile dysfunction. As a brain-penetrant MC4R agonist, it can modulate central pathways involved in sexual function. The compound's in vivo effects are mediated through MC4R activation. Its selectivity for MC4R over other melanocortin receptors reduces off-target effects. Specific in vivo efficacy data have been reported in preclinical models of erectile dysfunction. The compound has also been studied for its effects on food intake and energy homeostasis. |
| Enzyme Assay |
The in vitro assay for PF-00446687 typically involves measuring MC4R activation using a cAMP accumulation assay. HEK293 cells expressing MC4R are treated with varying concentrations of PF-00446687, and cAMP levels are measured using ELISA or HTRF assays. The EC50 of 12 +/- 1 nM is determined from dose-response curves. Selectivity is confirmed by testing the compound against cells expressing MC1R, MC3R, and MC5R. Data are analyzed using nonlinear regression models to determine potency and efficacy.
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| Cell Assay |
In vitro cellular assays for PF-00446687 are conducted using HEK293 cells or other cell lines expressing melanocortin receptors (MC1R, MC3R, MC4R, MC5R). Cells are treated with varying concentrations of PF-00446687. Receptor activation is assessed by measuring cAMP accumulation using ELISA or HTRF assays. The compound's potency and selectivity are determined from dose-response curves. Cell viability is assessed to ensure that the observed effects are not due to cytotoxicity. All experiments are performed in triplicate with appropriate controls.
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| Animal Protocol |
In vivo animal studies for PF-00446687 are typically performed in rodent models of erectile dysfunction or feeding behavior. For erectile dysfunction studies, animals are treated with the compound, and erectile function is assessed by measuring intracavernosal pressure or by observing mating behavior. For feeding studies, food intake and body weight are monitored. The compound is administered via intraperitoneal or oral routes. Standard study designs with vehicle control and positive control groups are employed. Specific protocols are described in the literature.
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| ADME/Pharmacokinetics |
Pharmacokinetic data for PF-00446687 indicate that it is brain-penetrant. The compound has a molecular weight of 470.59 g/mol and a molecular formula of C28H36F2N2O2. It is a small molecule with properties suitable for oral bioavailability. Specific pharmacokinetic parameters such as half-life, Cmax, and bioavailability are not provided in the available sources. The compound is for research use only. Storage recommendations are not provided in the available sources.
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| Toxicity/Toxicokinetics |
Toxicology data for PF-00446687 are not extensively reported. As an MC4R agonist, the compound's safety profile would be related to its effects on energy homeostasis, sexual function, and other MC4R-mediated processes. Potential side effects could include changes in appetite, body weight, and sexual function. Specific toxicity data, including LD50 values and organ toxicity profiles, are not available. The compound is for research use only.
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| References |
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| Additional Infomation |
PF-00446687 has been studied for the treatment of erectile dysfunction.
PF-00446687 is a potent, selective melanocortin-4 receptor (MC4R) agonist with an EC50 of 12 +/- 1 nM. It is brain-penetrant and selectively activates MC4R over MC1R, MC3R, and MC5R. The compound has been investigated for the treatment of erectile dysfunction and is also reported to be a JAK3 inhibitor. It has a molecular weight of 470.59 g/mol and a molecular formula of C28H36F2N2O2. PF-00446687 is a research tool for studying MC4R biology. |
| Molecular Formula |
C28H36N2O2F2
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| Molecular Weight |
470.59444
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| Exact Mass |
470.274
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| CAS # |
862281-92-3
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| PubChem CID |
11328898
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| Appearance |
White to off-white solid powder
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| LogP |
4.656
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
34
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| Complexity |
708
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| Defined Atom Stereocenter Count |
4
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| SMILES |
C[C@@H]1CN(C[C@@H](C1(C2=CC=CC=C2)O)C)C(=O)[C@@H]3CN(C[C@H]3C4=C(C=C(C=C4)F)F)C(C)(C)C
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| InChi Key |
WHPJOAUPIZDJNX-YTEQHECZSA-N
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| InChi Code |
InChI=1S/C28H36F2N2O2/c1-18-14-31(15-19(2)28(18,34)20-9-7-6-8-10-20)26(33)24-17-32(27(3,4)5)16-23(24)22-12-11-21(29)13-25(22)30/h6-13,18-19,23-24,34H,14-17H2,1-5H3/t18-,19+,23-,24+,28?/m0/s1
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| Chemical Name |
[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]-[(3S,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl]methanone
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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 : ~62.5 mg/mL (~132.81 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.42 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.42 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.42 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1250 mL | 10.6250 mL | 21.2499 mL | |
| 5 mM | 0.4250 mL | 2.1250 mL | 4.2500 mL | |
| 10 mM | 0.2125 mL | 1.0625 mL | 2.1250 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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