| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
Purity: ≥98%
PF-592379 (PF592379) is a novel, potent and selective agonist of dopamine D3 receptor agonist (EC50 = 21 nM) with the potential for the treatment of male erectile dysfunction and female sexual dysfunction. opamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. In vivo, PF-592379 has low-moderate clearance relative to liver blood flow of 6.3 and 8.5 ml/min/kg in dog and 44.8 and 58.2 ml/min/kg in rat. It has high permeability in Caco-2 cells and was completely absorbed in rat and dog pharmacokinetic studies with an oral bioavailability of 28% in both rats and 61 and 87% in the dogs. These data are consistent with the physicochemical properties of PF-592379, which indicate complete absorption by the transcellular route. Elimination of PF-592379 was predominantly metabolic in nature. In vitro routes of metabolism studies indicate that metabolism in the rat is a combination of P450 mechanisms and N-glucuronidation, whereas in dog and human, N-glucuronidation is the major route. NMR analysis indicates that N-glucuronidation is non-quaternary in nature and occurs on both the pyridyl amine and ring nitrogen. Rates of clearance via N-glucuronidation were predicted to be low in humans compared with acyl or phenolic glucuronidation. PF-592379 was predicted to have complete absorption from the gastrointestinal tract and an oral bioavailability of >60% in the clinic. Clinical data verified that PF-592379 is a low clearance compound in human, with a mean oral clearance of 6.5 ml/min/kg following a 200 mg oral dose. PF-592379 has ideal pharmacokinetic properties for an oral D3 agonist, intended for on demand dosing.
PF-592379 (5-[(2R,5S)-5-methyl-4-propylmorpholin-2-yl]pyridin-2-amine) is a potent, selective, orally active full agonist of the dopamine D3 receptor. It was developed for the treatment of male erectile dysfunction and female sexual dysfunction. The compound demonstrates high permeability in Caco-2 cells and is completely absorbed in preclinical species. PF-592379 has ideal pharmacokinetic properties for an oral D3 agonist intended for on-demand dosing. Unlike less selective D3-preferring agonists, PF-592379 shows high functional selectivity (>470-fold) for D3 over D2 receptors, and preclinical studies in rats indicate it lacks cocaine-like reinforcing or discriminative stimulus effects, suggesting low abuse potential. [1][2][3]| Targets |
PF-592379 is a full agonist of the dopamine D3 receptor (D3R). In vitro binding affinity (Ki) for the human D3 receptor is 215 nM (95% CI: 157-293 nM). For the human D4 receptor, Ki is 4165 nM (95% CI: 3670-4727 nM). It shows no significant binding to D2, D1, or D5 receptors at concentrations up to 10 μM. [2][3]
In vitro functional activity at the human D3 receptor (cAMP accumulation assay) shows an EC50 of 21 nM (95% CI: 18-30 nM) with Emax of 95% (89-103%), indicating full agonist activity. At the human D4 receptor, EC50 is 3.9 μM (95% CI: 1.6-5.5 μM). No functional activity is observed at the D2 receptor (EC50 > 10 μM), demonstrating >470-fold functional selectivity for D3 over D2. [2][3] |
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| ln Vitro |
PF-592379 shows high permeability in Caco-2 cells, consistent with complete absorption by the transcellular route. [1]
In vitro metabolism studies indicate that in rat, metabolism is a combination of P450 mechanisms and N-glucuronidation, whereas in dog and human, N-glucuronidation is the major route. NMR analysis indicates N-glucuronidation is non-quaternary in nature and occurs on both the pyridyl amine and ring nitrogen. Rates of clearance via N-glucuronidation are predicted to be low in humans compared with acyl or phenolic glucuronidation. [1] In vitro, PF-592379 functions as a full agonist at the D3 receptor (EC50 = 21 nM) and has no agonist activity at the D2 receptor (EC50 > 10 μM). [2][3] PF-592379 appears to be a complete agonist (Emax=95%) in comparison to normal pramipexole, a D2/D3 receptor agonist used to treat Parkinson's disease [1]. The dopamine 3 agonist PF-592379 is a strong and selective one, with EC50 and Ki values of 21 nM and 322 nM, respectively[2]. PF-592379 (PF-592,379) preferentially and highly affinitively binds to the human D3 receptor (Ki=215 nM), according to in vitro binding studies. PF-592379 has binding selectivity for the human D3 receptor that is 19 times larger than that of the D4 receptor, despite the fact that it also binds to the human D4 receptor (Ki=4165 nM). At dosages up to 10 µM, PF-592379 is preferred to D3 over D2, D1, and D5 receptors since it is unable to bind human D2 (Ki≥10 μM), D1 (Ki≥10 μM), or D5 (Ki≥10 μM) receptors [3]. |
| ln Vivo |
PF-592379 (0.32 mg/kg/inj, i.v.) fails to maintain self-administration in experimentally naive rats under an FR1 schedule of reinforcement; responding occurs at very low rates and decreases over time. In cocaine-trained rats, PF-592379 (0.01-1.0 mg/kg/inj, i.v.) maintains saline-like rates of responding when substituted under FR5 or progressive ratio (PR) schedules of reinforcement. [3]
In rats trained to discriminate cocaine (5.6 mg/kg, i.p.) from saline, PF-592379 (0.32-32.0 mg/kg, s.c.) produces nearly exclusive responding on the saline-appropriate lever, with maximum of 3.5% cocaine-appropriate responding observed, indicating lack of cocaine-like interoceptive effects. [3] In rat models of erectile function, PF-592379 produces proerectile effects consistent with D3 receptor agonism (data referenced but not detailed in these papers). [2] In clinical studies (healthy volunteers and osteoarthritis patients), PF-592379 does not produce adverse events suggestive of abuse potential, including no reports of euphoric mood, feeling drunk, or disorientation, unlike oxycodone comparator. [3] PF-592379 is an oral dopamine-3 agonist for rats and dogs. PF-592379 has low-to-moderate clearance relative to hepatic blood flow in dogs, ranging from 6.3 and 8.5 mL/min/kg in dogs to 44.8 and 58.2 mL/min/kg in rats. It is extremely permeable in Caco-2 cells and was entirely absorbed in pharmacokinetic experiments in rats and dogs, with oral bioavailability of 28% in rats and 61% in dogs, respectively. 87%[1]. |
| Enzyme Assay |
cAMP accumulation functional assay: CHO cells stably expressing recombinant human dopamine receptors (D2, D3, D4) were plated at 15,000 cells/well 48 hours prior to the experiment. Cells were incubated in serum-free medium for 1 hour before the addition of fresh medium containing 100 μM forskolin, 100 μM isobutyl methylxanthine, and varying concentrations of PF-592379. cAMP accumulation was allowed to proceed for 15 minutes at room temperature, and reactions were terminated by removing the medium and adding cold 7.5% trichloroacetic acid. Samples were diluted and assayed by radioimmunoassay. PF-592379 showed EC50 of 21 nM (D3) and 3.9 μM (D4), with no activity at D2 (EC50 >10 μM). [2][3]
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| Animal Protocol |
Acquisition of self-administration in naive rats: Male Sprague-Dawley rats with indwelling jugular vein catheters were placed in operant chambers equipped with three levers (one active, two inactive). PF-592379 (0.32 mg/kg/inj) was available for i.v. self-administration under an FR1 TO20-sec schedule of reinforcement. Sessions were 2 hours, conducted 5 days per week for 18 sessions. Acquisition criteria: ≥15 injections/session and ≥70% responding on active lever over 3 consecutive sessions. [3]
Substitution studies in cocaine-trained rats (FR5 and PR schedules) : Rats trained to self-administer 1.0 mg/kg/inj cocaine under FR5 schedule were used. Saline substitution preceded dose substitution. PF-592379 (0.01-1.0 mg/kg/inj, i.v.) was evaluated, with each dose available for at least two consecutive 2-hour sessions. Under PR schedule, response requirement incremented after each injection; sessions terminated after 1-hour limited hold or 6 hours. [3] Drug discrimination: Rats were trained to discriminate 5.6 mg/kg cocaine (i.p.) from saline under a two-lever FR10 food-reinforced task. After stable discrimination (≥80% correct first ratio, ≥90% total session correct), substitution tests were conducted with PF-592379 (0.32-32.0 mg/kg, s.c.), administered 5 minutes pre-session. Test sessions lasted 25 minutes, with food available for completion of FR10 on either lever. [3] |
| ADME/Pharmacokinetics |
In rat, PF-592379 has moderate clearance relative to liver blood flow, with clearance values of 44.8 and 58.2 ml/min/kg. Oral bioavailability in rat is 28%. [1]
In dog, PF-592379 has low-moderate clearance relative to liver blood flow (6.3 and 8.5 ml/min/kg), with oral bioavailability of 61% and 87%. [1] In human, PF-592379 is a low clearance compound, with a mean oral clearance of 6.5 ml/min/kg following a 200 mg oral dose. Predicted oral bioavailability in the clinic is >60%. The compound is completely absorbed from the gastrointestinal tract. A single i.v. dose of 0.1 mg/kg produces estimated free drug plasma levels ~140-fold greater than the EC50 at D3 receptors; a single i.v. dose of 2 mg/kg produces free drug levels ~1400-fold greater than EC50. [1][3] |
| Toxicity/Toxicokinetics |
In clinical studies (healthy volunteers and osteoarthritis patients), PF-592379 did not produce any adverse events suggestive of abuse potential, including no reports of euphoric mood, feeling drunk, or disorientation (unlike the oxycodone comparator). In a study using a cognitive test battery, PF-592379 did not elicit cognitive changes typically associated with drugs of abuse. In animal studies, high doses (up to 32 mg/kg, s.c.) produced only mild inhibition of locomotor activity. [3]
|
| References |
[1]. Pharmacokinetics and elucidation of the rates and routes of N-glucuronidation of PF-592379, an oral dopamine 3 agonist in rat, dog, and human. Xenobiotica. 2010 Nov;40(11):730-42.
[2]. Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects. ACS Chem Neurosci. 2017 Jan 18;8(1):165-177. [3]. Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats. Behav Pharmacol. 2012 Jun;23(3):280-91 |
| Additional Infomation |
N-glucuronidation: PF-592379 is primarily eliminated via N-glucuronidation in humans. NMR analysis shows glucuronidation occurs on both the pyridyl amine and ring nitrogen. This N-glucuronidation is unique compared to acyl or phenolic glucuronidation, and rates are predicted to be low in humans. [1]
Abuse potential assessment: PF-592379 lacks cocaine-like reinforcing or discriminative stimulus effects in rat models. In clinical studies, it does not produce euphoria or other abuse-related adverse events. This low abuse potential is attributed to its high selectivity for D3 over D2 receptors (>470-fold functionally), as D2 receptor activity appears necessary for abuse-related effects. [3] CNS penetration: PF-592379 has good CNS penetration with a CSF to unbound plasma concentration ratio of 0.8-1.0. [3] Metabolic stability: PF-592379 is metabolized via a combination of P450 mechanisms and N-glucuronidation in rat, while N-glucuronidation is the major route in dog and human. [1] |
| Molecular Formula |
C13H21N3O
|
|---|---|
| Molecular Weight |
235.3253428936
|
| Exact Mass |
235.168
|
| Elemental Analysis |
C, 66.35; H, 8.99; N, 17.86; O, 6.80
|
| CAS # |
710655-15-5
|
| PubChem CID |
10263487
|
| Appearance |
Typically exists as solid at room temperature
|
| LogP |
1.3
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
3
|
| Heavy Atom Count |
17
|
| Complexity |
237
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
CCCN1C[C@H](OC[C@@H]1C)C2=CN=C(C=C2)N
|
| InChi Key |
DFTCYTDJDXZFSK-JQWIXIFHSA-N
|
| InChi Code |
InChI=1S/C13H21N3O/c1-3-6-16-8-12(17-9-10(16)2)11-4-5-13(14)15-7-11/h4-5,7,10,12H,3,6,8-9H2,1-2H3,(H2,14,15)/t10-,12-/m0/s1
|
| Chemical Name |
5-[(2R,5S)-5-methyl-4-propylmorpholin-2-yl]pyridin-2-amine
|
| Synonyms |
PF592379; PF 592379; PF-592,379; 710655-15-5; 66B7UY5K7I; 5-((2R,5S)-5-Methyl-4-propylmorpholin-2-yl)pyridin-2-amine; PF-592,379; PF-592379.
|
| 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)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 4.2494 mL | 21.2468 mL | 42.4935 mL | |
| 5 mM | 0.8499 mL | 4.2494 mL | 8.4987 mL | |
| 10 mM | 0.4249 mL | 2.1247 mL | 4.2494 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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