SERP
Comments:
My rating refers to using this compound as a partial agonist ONLY. Other compounds are available that display full agonist properties, as described in 10.1371/journal.pone.0046300. Based on the available data AMG-837 can be used in cell based assays, primary pancreatic islet assays and in animal models within the stated concentrations (see comment re reviewer’s limited knowledge of pharmacokinetics below).
In this case, it was difficult to decide on the most appropriate rating. A 3-star rating suggests that this is the best available tool, which seems too generous of a statement in this case given the limitations I mentioned. On the other hand, a 2-star rating suggests that the characterization was incomplete and inconclusive. In this case, I think the data is there and relatively complete, so this rating seems too harsh. Yet, although I do think that this compound is suitable for use, I do think that there have been developments in this space since 2012 that reported better probes/tool compounds for this target. Additionally, as mentioned, I really urge potential users to read the background literature before using this or any other tools for this target.
However, there are couple of issues to note:
- a potential target space beyond small number (<70 GPCRs out of more than 800) has not been examined
- no negative control compounds are available
- highly bound ( 98.7%) to human plasma; this did not interfere with results in rat (reference: https://doi.org/10.1371/journal.pone.0027270), and Cmax in mouse, rat, dog and monkey was in low M range (reference: DOI 10.1016/j.bmcl.2011.10.118).
General comments:
- Full agonists for FFAR1 (GPR40) have been reported; depending on type of questions being asked, full agonists may be more appropriate than a compound like AMG-837, which is a partial agonist with ago-allosteric mechanism.
- AMG-837 compound affects only signaling through Gq (and not Gs) pathway.
- The compound (AMG-837) and its target (FFAR1) have complicated pharmacology (mechanism of action), with a lot of mechanistic subtlety so this reviewer recommends spending time with primary and review literature to learn about the target and the compounds (including endogenous ligands) that it binds.
- AMG-837 and structurally related compounds display significantly different pharmacology, suggesting that SAR is hard to deduce.
- AMG-837 is highly lipophilic (cLog P = 7.6) and likely to have significant CNS exposure, so care needs to be taken when used in vivo to account for possible CNS exposure.
- Reviewer is not an expert on pharmacokinetics, so take the comments re in vivo dose and use with these limitations in mind.
Additional background references: doi: 10.1124/mol.112.079640; 10.1016/j.molmet.2014.10.002; 10.1016/j.bmcl.2021.127969; 10.1021/ml400501
