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Purity: ≥98%
AM-1638 (AMG-1638) is a novel, potent and orally bioavailable GPR40/FFA1 full agonist (EC50=0.16 μM) with antidiabetic activity. GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels.
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| ln Vitro |
Further increasing the size of the R2 substituent to 5,5-dimethylcyclopentenyl moiety provides a GPR40 full agonist that displays the requisite potency in the presence of 100% human serum (Table 3; 21/AMG1638, 0.71 μM) to warrant evaluation in vivo. In contrast, the enantiomer of full agonist 21 is both less potent and a partial agonist (Table 3; 22, 34 μM, 71%) [1].
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| ln Vivo |
Full agonist 21/AMG1638 and partial agonist 1 were compared at a dose of 60 mg/kg for their ability to improve glycemic control in BDF mice with diet-induced obesity (DIO), a model of type II diabetes that develops elevated blood glucose and impaired glucose tolerance.14 Both compounds reduce blood glucose excursion (Figure 2A; 1 [glucose]max 317 mg/dL; 21/AMG1638, [glucose]max 204 mg/dL) and area under the curve of blood glucose (AUC 0–60 min) (Figure 2B) upon administration 1 h before an oral glucose tolerance test (OGTT) as compared to the control (Figure 2A; control [glucose]max 462 mg/dL). However, full agonist 21/AMG1638 shows greater efficacy in blunting glucose excursion than partial agonist 1. Moreover, full agonist 21/AMG1638 imparts greater 46% improvement in AUCglucose, while partial agonist 1 provides 34%. Partial agonist 1 does not display a statistically significant increase in plasma insulin as compared to the control. However, full agonist 21 elicits a statistically significant increase in both plasma insulin at all time points and in the AUCinsulin (Figure 2C,D). This is in accord with our original hypothesis and further confirms that the greater intrinsic efficacy observed in vitro for full agonist 21 affords advantages in vivo for maintaining plasma glucose homeostasis as compared to partial agonist 1.[1]
AM-1638 has plasma half-lives appropriate for assessing its antidiabetic effects in mice, rats, and cynomologus monkeys due to its moderate cross-species plasma clearance and volume of distribution. Furthermore, full agonist AM-1638 has great oral bioavailability when administered orally (>100% in mice, 72% in rats, and 71% in cyno). In BDF/DIO mice, AM-1638 demonstrates antidiabetic activity[1]. |
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| Cell Assay |
Aequorin assay: [1]
A cell-based aequorin assay may be employed to characterize the modulatory activity of compounds on the GPR40 signaling pathway. CHO cells are transfected in a 15 cm plate containing 14 million cells with 5 µg or 0.05 µg of GPR40 expression vector and 5 µg or 0.05 µg of Aequorin expression vector using Lipofectamine 2000. After 17–24 hours post-transfection, cells are washed with phosphate buffered saline (PBS) and detached from the tissue culture dish with 2 mL of trypsin (0.25%(w/v)). Trypsinization is halted with 28 mL of Hanks Buffered Salt Solution containing 20 mM Hepes (H/HBSS) and 0.01% fatty acid-free bovine serum albumin (BSA) or 0.625% fatty acid-free human serum albumin (HSA). Coelantrazine is added to 1 ug/mL and the cells are incubated for 2 hours at room temperature. Cells are gently mixed every 15 minutes. Compounds are dissolved in dimethyl sulfoxide for preparation of 10 mM stock solutions. Compounds are diluted in H/HBSS containing 0.01% BSA. Serial dilutions of the test compounds are prepared to determine dose response. Aequorin luminescence measurements are made using an EG&G Berthold 96-well luminometer and the response is measured over a 20 second interval after cells and compounds were mixed. The area-under-curve from 2–20 seconds is plotted to determine dose reponse. The EC50 (effective concentration to reach 50% maximal response) is determined from the dose response plot. The mean realative standard error for this assay is 14%. |
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| Animal Protocol |
In vivo procedures: [1]
Male B6D2F1/J mice were maintained on irradiated normal chow (Teklad 2918) until 5-weeks of age, and the switched to a high fat diet (60 kCal% fat) for 8-weeks to induce obesity and insulin resistance. Animals were housed in a room adjusted to a 12-h light/12-h dark cycle beginning at 0600 and 1800, respectively. Mice were allowed ad libidum access to regular chow and water. AMG 837 (1) and AMG1638 (21) were formulated for oral dosing using 1% hydroxypropyl methylcellulose (HPMC), 10% hydroxypropyl-beta cyclodextrin (HPBCD), 1% Tween 80. On the morning of the experiment, animals were fasted for four hours and body weight and blood glucose levels were measured. Animals were randomized into treatment groups based on these two parameters. Treatments were administered by oral gavage and sixty minutes later, the mice received a 2 g/kg glucose challenge dose by oral gavage (defined as t = 0 min). Blood samples were collected at -60, 0, 15, 30, 60, 90 and 120 minutes via tail vein relative to the glucose challenge. Glucose levels were monitored with a glucometer. Plasma insulin was measured using a mouse insulin ELISA kit. |
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| ADME/Pharmacokinetics |
Importantly, full agonist 21/AMG1638 exhibits moderate cross-species plasma clearance and volume of distribution, resulting in plasma half-lives suitable for evaluation of its antidiabetic properties in mouse, rat, and cynomologus monkey (Table 4). Moreover, oral administration of full agonist 21/AMG1638 demonstrates excellent oral bioavailability (mouse, >100%; rat, 72%; and cyno, 71%), affording the GPR40 full agonist 21/AMG1638 and the appropriate pharmacokinetic properties for comparison in vivo to the partial agonist 1.[1]
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| References | ||
| Additional Infomation |
GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (1), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist 1 to the structurally and pharmacologically distinct GPR40 full agonist AMG1638 (21). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist 21 exhibits in BDF/DIO mice as compared to partial agonist 1. [1]
In conclusion, we have described the SAR leading from the GPR40 partial agonist 1 to a structurally and pharmacologically distinct series of GPR40 agonists, exemplified by the orally bioavailable GPR40 full agonist 21/AMG1638. The antidiabetic activity that full agonist 21 exhibits in BDF/DIO mice provides compelling evidence that GPR40 full agonists afford access to a powerful mechanism for maintaining glycemic control and great potential for the treatment of type II diabetic patients. |
| Molecular Formula |
C33H35O4F
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|---|---|
| Molecular Weight |
514.627
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| Exact Mass |
514.252
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| Elemental Analysis |
C, 77.02; H, 6.86; F, 3.69; O, 12.44
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| CAS # |
1142214-62-7
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| PubChem CID |
57706778
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| Appearance |
Off-white to yellow solid powder
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| LogP |
8.252
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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 |
10
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| Heavy Atom Count |
38
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| Complexity |
835
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1(CCC=C1C2=C(C=CC(=C2)COC3=CC=CC(=C3)[C@@H](CC(=O)O)C4CC4)C5=C(C=CC(=C5)OC)F)C
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| InChi Key |
CHEANNSDVJOIBS-MHZLTWQESA-N
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| InChi Code |
InChI=1S/C33H35FO4/c1-33(2)15-5-8-30(33)28-16-21(9-13-26(28)29-18-24(37-3)12-14-31(29)34)20-38-25-7-4-6-23(17-25)27(19-32(35)36)22-10-11-22/h4,6-9,12-14,16-18,22,27H,5,10-11,15,19-20H2,1-3H3,(H,35,36)/t27-/m0/s1
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| Chemical Name |
(3S)-3-cyclopropyl-3-[3-[[3-(5,5-dimethylcyclopenten-1-yl)-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]phenyl]propanoic acid
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| Synonyms |
AM-1638; 1142214-62-7; Tris(2,2; (3S)-3-cyclopropyl-3-[3-[[3-(5,5-dimethylcyclopenten-1-yl)-4-(2-fluoro-5-methoxyphenyl)phenyl]methoxy]phenyl]propanoic acid; CHEMBL2152070; (S)-3-Cyclopropyl-3-(3-((2-(5,5-dimethylcyclopent-1-en-1-yl)-2'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methoxy)phenyl)propanoic acid; SCHEMBL2495289; DTXSID001102788;
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 : ~100 mg/mL (~194.31 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.86 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.04 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.04 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 | 1.9431 mL | 9.7157 mL | 19.4314 mL | |
| 5 mM | 0.3886 mL | 1.9431 mL | 3.8863 mL | |
| 10 mM | 0.1943 mL | 0.9716 mL | 1.9431 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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