Synonym
PF-06827443; PF 06827443; PF06827443; PF-6827443; PF 6827443; PF6827443.
IUPAC/Chemical Name
2-((3R,4S)-3-Hydroxytetrahydro-pyran-4-yl)-5-methyl-6-(4-oxazol-4-yl-benzyl)-2,3-dihydro-isoindol-1-one
InChi Key
RBMHKFVYRIRMOG-GOTSBHOMSA-N
InChi Code
InChI=1S/C24H24N2O4/c1-15-8-19-11-26(22-6-7-29-13-23(22)27)24(28)20(19)10-18(15)9-16-2-4-17(5-3-16)21-12-30-14-25-21/h2-5,8,10,12,14,22-23,27H,6-7,9,11,13H2,1H3/t22-,23-/m0/s1
SMILES Code
O=C1N([C@@H]2[C@@H](O)COCC2)CC3=C1C=C(CC4=CC=C(C5=COC=N5)C=C4)C(C)=C3
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
PF-06827443 is a potent, low-clearance, orally bioavailable, and CNS-penetrant M1-selective PAM with minimal agonist activity.
In vitro activity:
This study reports that PF-06827443 is an allosteric agonist in cell lines expressing rat, dog, and human M1 and use of inducible cell lines shows that agonist activity of PF-06827443 is dependent on receptor reserve. Furthermore, PF-06827443 is an agonist in native tissue preparations and induces behavioral convulsions in mice similar to other ago-PAMs. These findings suggest that PF-06827443 is a robust ago-PAM, independent of species, in cell lines and native systems.
Reference: ACS Chem Neurosci. 2018 Sep 19;9(9):2218-2224. https://pubmed.ncbi.nlm.nih.gov/29683646/
In vivo activity:
The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M1-selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity.
Reference: J Med Chem. 2017 Aug 10;60(15):6649-6663. https://pubmed.ncbi.nlm.nih.gov/28598634/
Preparing Stock Solutions
The following data is based on the
product
molecular weight
404.47
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Moran SP, Cho HP, Maksymetz J, Remke DH, Hanson RM, Niswender CM, Lindsley CW, Rook JM, Conn PJ. PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems. ACS Chem Neurosci. 2018 Sep 19;9(9):2218-2224. doi: 10.1021/acschemneuro.8b00106. Epub 2018 Apr 25. PMID: 29683646; PMCID: PMC6146053.
2. Davoren JE, Garnsey M, Pettersen B, Brodney MA, Edgerton JR, Fortin JP, Grimwood S, Harris AR, Jenkinson S, Kenakin T, Lazzaro JT, Lee CW, Lotarski SM, Nottebaum L, O'Neil SV, Popiolek M, Ramsey S, Steyn SJ, Thorn CA, Zhang L, Webb D. Design and Synthesis of γ- and δ-Lactam M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity. J Med Chem. 2017 Aug 10;60(15):6649-6663. doi: 10.1021/acs.jmedchem.7b00597. Epub 2017 Jul 26. PMID: 28598634.
In vitro protocol:
1. Moran SP, Cho HP, Maksymetz J, Remke DH, Hanson RM, Niswender CM, Lindsley CW, Rook JM, Conn PJ. PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems. ACS Chem Neurosci. 2018 Sep 19;9(9):2218-2224. doi: 10.1021/acschemneuro.8b00106. Epub 2018 Apr 25. PMID: 29683646; PMCID: PMC6146053.
2. Davoren JE, Garnsey M, Pettersen B, Brodney MA, Edgerton JR, Fortin JP, Grimwood S, Harris AR, Jenkinson S, Kenakin T, Lazzaro JT, Lee CW, Lotarski SM, Nottebaum L, O'Neil SV, Popiolek M, Ramsey S, Steyn SJ, Thorn CA, Zhang L, Webb D. Design and Synthesis of γ- and δ-Lactam M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity. J Med Chem. 2017 Aug 10;60(15):6649-6663. doi: 10.1021/acs.jmedchem.7b00597. Epub 2017 Jul 26. PMID: 28598634.
In vivo protocol:
1. Moran SP, Cho HP, Maksymetz J, Remke DH, Hanson RM, Niswender CM, Lindsley CW, Rook JM, Conn PJ. PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems. ACS Chem Neurosci. 2018 Sep 19;9(9):2218-2224. doi: 10.1021/acschemneuro.8b00106. Epub 2018 Apr 25. PMID: 29683646; PMCID: PMC6146053.
2. Davoren JE, Garnsey M, Pettersen B, Brodney MA, Edgerton JR, Fortin JP, Grimwood S, Harris AR, Jenkinson S, Kenakin T, Lazzaro JT, Lee CW, Lotarski SM, Nottebaum L, O'Neil SV, Popiolek M, Ramsey S, Steyn SJ, Thorn CA, Zhang L, Webb D. Design and Synthesis of γ- and δ-Lactam M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity. J Med Chem. 2017 Aug 10;60(15):6649-6663. doi: 10.1021/acs.jmedchem.7b00597. Epub 2017 Jul 26. PMID: 28598634.
Rook JM, Bertron JL, Cho HP, Garcia-Barrantes PM, Moran SP, Maksymetz JT, Nance KD, Dickerson JW, Remke DH, Chang S, Harp JM, Blobaum AL, Niswender CM, Jones CK, Stauffer SR, Conn PJ, Lindsley CW. A Novel M1 PAM VU0486846 Exerts Efficacy in Cognition Models without Displaying Agonist Activity or Cholinergic Toxicity. ACS Chem Neurosci. 2018 Sep 19;9(9):2274-2285. doi: 10.1021/acschemneuro.8b00131. Epub 2018 May 8. PMID: 29701957; PMCID: PMC6146057.
Moran SP, Cho HP, Maksymetz J, Remke DH, Hanson RM, Niswender CM, Lindsley CW, Rook JM, Conn PJ. PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems. ACS Chem Neurosci. 2018 Sep 19;9(9):2218-2224. doi: 10.1021/acschemneuro.8b00106. Epub 2018 Apr 25. PMID: 29683646; PMCID: PMC6146053.
Davoren JE, Garnsey M, Pettersen B, Brodney MA, Edgerton JR, Fortin JP, Grimwood S, Harris AR, Jenkinson S, Kenakin T, Lazzaro JT, Lee CW, Lotarski SM, Nottebaum L, O'Neil SV, Popiolek M, Ramsey S, Steyn SJ, Thorn CA, Zhang L, Webb D. Design and Synthesis of γ- and δ-Lactam M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity. J Med Chem. 2017 Aug 10;60(15):6649-6663. doi: 10.1021/acs.jmedchem.7b00597. Epub 2017 Jul 26. PMID: 28598634.
