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Purity: ≥98%
PF-5190457 is a novel, potent, orally available and selective ghrelin receptor inverse agonist with a pKi of 8.36. PF-5190457 stimulates human islets with glucose to effectively increase insulin secretion. The ghrelin receptor pharmacology and off-target selectivity of PF-5190457 are better balanced. Clinical trials involving humans were initiated for PF-5190457 due to its encouraging safety and pharmacological profile.
| Targets |
Humnan ghrelin receptor ( pKi = 8.36 )
PF-5190457 possesses an optimal ratio between off-target selectivity and ghrelin receptor pharmacology[1]. |
|---|---|
| ln Vitro |
PF-5190457 possesses an optimal ratio between off-target selectivity and ghrelin receptor pharmacology[1].
PF-5190457 is a potent and selective ghrelin receptor inverse agonist. In a human ghrelin receptor scintillation proximity assay (SPA) binding assay, it exhibited a pKi of 8.36 ± 0.18. In a GTPγS functional assay, it showed inverse agonist activity with a functional pKi of 8.18 ± 0.06 and a minimum percent effect of -29%. [1] In a muscarinic M2 β-Arrestin PathHunter functional assay, PF-5190457 demonstrated a pKi of 5.71 ± 0.08, resulting in a selectivity ratio (M2 Ki / ghrelin receptor functional Ki) of 266. [1] In a broad ligand promiscuity profiling panel (CEREP) screened at 10 µM, PF-5190457 showed minimal off-target activity. Only serotonin 5-HT2B was inhibited >50% (IC50 = 3700 nM). Follow-up functional assays confirmed it had no agonist or antagonist activity at the 5-HT2B receptor. [1] PF-5190457 exhibited moderate inhibition of the human ether-à-go-go-related gene (hERG) channel with an IC50 of 6.9 µM. [1] |
| ln Vivo |
PF-5190457 has strong increases in glucose-stimulated insulin secretion in human whole and dispersed islets, along with excellent selectivity[1].
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| Enzyme Assay |
The human ghrelin receptor binding assay utilized a scintillation proximity assay (SPA) format as previously published. The assay measures compound displacement of a radioligand from the receptor. [1]
The human ghrelin receptor functional assay utilized a GTPγS binding format as previously published. This assay measures the compound's effect on receptor-mediated G-protein activation, distinguishing agonists, antagonists, and inverse agonists. [1] The muscarinic M2 receptor functional assay utilized a β-Arrestin PathHunter assay. The assay measures compound inhibition of agonist (oxotremorine)-induced β-arrestin recruitment. Ki values for antagonists were determined in the presence of an EC80 concentration of oxotremorine. [1] |
| Cell Assay |
Glucose-stimulated insulin secretion (GSIS) was assessed in human whole islets in static culture. Human islets were incubated with low (2.8 mM) and high (11.2 mM) glucose concentrations to establish glucose responsiveness. PF-5190457 (1 µM) or the positive control glibenclamide was added. Insulin secretion into the medium was measured. PF-5190457 significantly increased insulin secretion above the high glucose control. [1]
Passive permeability (Papp) was measured using low-efflux MDCKII cells. Compounds were dosed on the apical (A) or basolateral (B) side, and appearance on the opposite side was measured over time to calculate permeability. [1] Multidrug resistance (MDR) efflux potential was assessed using MDCK cells transfected with human MDR1 (P-glycoprotein). The efflux ratio was calculated as the ratio of basolateral-to-apical (B-A) permeability over apical-to-basolateral (A-B) permeability. A ratio >2.5 typically indicates significant efflux and reduced central nervous system exposure. PF-5190457 had an efflux ratio of 7.2. [1] |
| Animal Protocol |
Pharmacokinetic studies were conducted in rats, dogs, and monkeys. Specific dosing details (formulation, route, frequency) for these studies are not provided in the manuscript. [1]
A portal vein cannulated rat model was used to assess absorption. The high observed in vivo clearance in standard rat PK studies prompted this experiment, which demonstrated excellent absorption (Fa = 100%) for PF-5190457, consistent with its high solubility and moderate passive permeability. [1] |
| ADME/Pharmacokinetics |
The crystalline PF-5190457 has a solubility of 0.18 mg/mL in water (pH 7.9), 4.57 mg/mL in phosphate-buffered saline (PBS, pH 6.7), and greater than 25 mg/mL in simulated gastric juice (SGF, pH 1.2). [1] The plasma protein binding rate (fu) in human plasma is 0.15. [1] The intrinsic clearance rate of human liver microsomes (HLM) (CLint) is 21 mL/min/kg (uncorrected free fraction). After correcting for microsome binding rate (fu,mic = 0.8) and plasma binding rate, the predicted human plasma clearance rate is lower (3.3 mL/min/kg). [1] Rat pharmacokinetics showed higher plasma clearance and volume of distribution. Pharmacokinetic studies in dogs and monkeys showed that plasma clearance and volume of distribution were at moderate levels. [1]
Human pharmacokinetics were predicted using preclinical data and a physiologically based pharmacokinetic (PBPK) model: absorption rate of 86%, bioavailability (F) of 67%, steady-state volume of distribution (Vdss) of 1.79 L/kg, and half-life (t1/2) of 6.3 hours. [1] Urinary and bile excretion contributed very little to total clearance in the studied species. [1] The equilibrium binding constant (Kd) of PF-5190457 to the auxin-releasing peptide receptor was determined to be 3.04 ± 0.91 nM using the Motulsky kinetic method. [1] To maintain a minimum free drug concentration of 10 × Kd (~30 nM) throughout the dosing interval, the expected oral dose for humans is 35 mg twice daily (bid). The corresponding predicted maximum free drug concentration (Cmax,u) and area under the free drug curve (AUCu) are 52.4 nM and 1010 nM·h, respectively. [1] |
| Toxicity/Toxicokinetics |
PF-5190457 showed moderate hERG channel inhibition with an IC50 of 6.9 µM. This value is more than 100 times higher than the predicted human free Cmax (52.4 nM), suggesting a low likelihood of clinically causing QTc interval prolongation. [1] In a broad non-target screening (CEREP) at a concentration of 10 µM, significant inhibition (>50%) was observed only on the 5-HT2B receptor (IC50 = 3700 nM). Subsequent functional studies confirmed that the drug has no agonist or antagonist activity against this receptor. [1] PF-5190457 has undergone a 1-month toxicology and safety pharmacology study in rats and dogs. Safety data showed a safety margin far exceeding the expected effective human exposure, supporting its continued development. [1]
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| References | |
| Additional Infomation |
PF-5190457 is being investigated in clinical trial NCT01522807 (a study of three formulations of PF-05190457 in healthy volunteers). PF-5190457 is the clinical candidate code for compound 16h, a spirocyclic aza-butanepiperidine derivative. It was discovered by optimizing a centrally acting auxin-releasing peptide receptor inverse agonist lead compound (compound 11) with the aim of obtaining a compound with limited peripheral action and higher selectivity. [1] The design strategy focused on improving lipophilic efficiency (LipE) to enhance the potency of the auxin-releasing peptide receptor while increasing overall polarity to reduce off-target pharmacological effects and central nervous system penetration. The LipE (based on elogD) of PF-5190457 is 6.9. [1] PF-5190457 is an inverse agonist of the auxin-releasing peptide receptor with high constitutive activity. The reverse agonist effect may provide greater in vivo therapeutic opportunities by reducing basal receptor signaling. [1] Its primary indication is type 2 diabetes mellitus (T2DM), based on the hypothesis that blocking ghrelin receptor signaling can improve glucose homeostasis and insulin sensitivity, partly because it acts directly on the islets of Langerhans, thereby increasing glucose-stimulated insulin secretion. [1] Based on its favorable pharmacological properties, selectivity, and safety results in non-clinical studies, PF-5190457 has entered the human clinical trial stage. [1]
|
| Molecular Formula |
C29H32N6OS
|
|---|---|
| Molecular Weight |
512.668984413147
|
| Exact Mass |
512.235
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| Elemental Analysis |
C, 67.94; H, 6.29; N, 16.39; O, 3.12; S, 6.25
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| CAS # |
1334782-79-4
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| PubChem CID |
58438464
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.757
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| LogP |
4.8
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
|
| Heavy Atom Count |
37
|
| Complexity |
842
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
S1C(C)=CN2C1=NC(=C2)CC(N1CCC2(CC1)CN([C@H]1C3C=CC(C4C=C(C)N=CN=4)=CC=3CC1)C2)=O
|
| InChi Key |
ZIUDADZJCKGWKR-AREMUKBSSA-N
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| InChi Code |
InChI=1S/C29H32N6OS/c1-19-11-25(31-18-30-19)22-3-5-24-21(12-22)4-6-26(24)35-16-29(17-35)7-9-33(10-8-29)27(36)13-23-15-34-14-20(2)37-28(34)32-23/h3,5,11-12,14-15,18,26H,4,6-10,13,16-17H2,1-2H3/t26-/m1/s1
|
| Chemical Name |
2-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-1-[2-[(1R)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone
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| Synonyms |
PF5190457; PF-05190457; PF-5190457; PF 5190457; PF05190457; PF 05190457
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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: ~250 mg/mL (~487.6 mM)
Ethanol: ~100 mg/mL (~195.1 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.88 mM) (saturation unknown) in 10% EtOH + 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 25.0 mg/mL clear EtOH 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: ≥ 2.5 mg/mL (4.88 mM) (saturation unknown) in 10% EtOH + 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 25.0 mg/mL clear EtOH 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: ≥ 2.5 mg/mL (4.88 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.08 mg/mL (4.06 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 of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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 5: ≥ 2.08 mg/mL (4.06 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. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9506 mL | 9.7529 mL | 19.5057 mL | |
| 5 mM | 0.3901 mL | 1.9506 mL | 3.9011 mL | |
| 10 mM | 0.1951 mL | 0.9753 mL | 1.9506 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01522807 | Completed | Drug: PF-05190457 | Diabetes Mellitus, Type 2 | Pfizer | September 2011 | Phase 1 |
| NCT01247896 | Completed | Drug: PF-05190457 | Diabetes Mellitus, Type II | Pfizer | December 2010 | Phase 1 |
| NCT02039349 | Completed | Drug: PF-05190457 | Alcoholism Alcohol Dependence |
National Institute on Alcohol Abuse and Alcoholism (NIAAA) |
January 3, 2014 | Phase 1 |
| NCT01372163 | Terminated | Drug: PF-05190457 or Placebo | Diabetes Mellitus, Type 2 | Pfizer | July 2011 | Phase 1 |
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