November 2018 Potency results

[mbhebhe]

Potency results for the samples sent last month #62 .

Sadly, all the novel S3 compounds in this shipment were inactive

Series 4:

• All 5-substituted compounds are inactive
• OSM-S-560, OSM-S-556, OSM-S-608, OSM-S-607 are active.
• All the rest inactive or slightly active
• Reference - 0.534 uM (for this batch) and 0.251, 0.301 (previous batches)

MMV number	OSM number	Internal number	Potency 1	Potency 2	Average
MMV1634446	OSM-S-606	MNB21-7	>25.11	>25.11	>25
MMV1634447	OSM-S-137	MNB45-2	7.685	6.065	6.875
MMV1634448	OSM-S-145	MJT17	>25.11	>25.11	>25
MMV1634449	OSM-S-649	MNB50-1	>25.11	>25.11	>25
MMV1634450	OSM-S-641	AP80	>25.11	>25.11	>25
MMV1634451	OSM-S-642	AP81	>25.11	>25.11	>25
MMV1634452	OSM-S-643	AP84	>25.11	>25.11	>25
MMV1634453	OSM-S-644	AP187	>25.11	>25.11	>25
MMV1634454	OSM-S-645	AP192	18.42	18.48	18.45
MMV1634455	OSM-S-646	AP193	>25.11	>25.11	>25
MMV1634456	OSM-S-647	AP196	>25.11	>25.11	>25
MMV1634457	OSM-S-648	AP197	>25.11	>25.11	>25
MMV1581295	OSM-S-556	DGS 81-1	0.139	0.152	0.146
MMV1581298	OSM-S-560	DGS 77-1	1.027	0.656	0.842
MMV1634420	OSM-S-634	MK147-1	>25.11	>25.11	>25
MMV1634421	OSM-S-591	DGS 90-1	>25.11	>25.11	>25
MMV1634422	OSM-S-589	DGS 89-2	>25.11	>25.11	>25
MMV1634423	OSM-S-588	DGS 88-2	>25.11	>25.11	>25
MMV1634424	OSM-S-638	DGS 94-1	>25.11	>25.11	>25
MMV1634425	OSM-S-631	MK128-1a	>25.11	>25.11	>25
MMV1634426	OSM-S-637	DGS 54-1	19.54	14.53	17.04
MMV1634427	OSM-S-539	DGS 55-1	13	10.04	11.52
MMV1634428	OSM-S-608	MK149-1a	0.256	0.308	0.282
MMV1634429	OSM-S-607	MK148-1	0.483	0.771	0.627
MMV1634430	OSM-S-635	MK059-1	>25.11	>25.11	>25
MMV1634431	OSM-S-636	MK091-2	>25.11	>25.11	>25
MMV1634432	OSM-S-623	MK114-1a	1.163	2.491	1.827
MMV1634433	OSM-S-624	MK115-1a	2.213	1.173	1.693
MMV1634434	OSM-S-626	MK127-1a	>25.11	>25.11	>25
MMV1634435	OSM-S-609	MK150-1a	7.678	4.586	6.132
MMV1634436	OSM-S-621	MK139-1	6.251	11.21	8.73
MMV1634437	OSM-S-622	MK126-1b	>25.11	>25.11	>25
MMV1634438	OSM-S-625	MK136-1	>25.11	>25.11	>25
MMV1634439	OSM-S-627	MK111-1b	>25.11	>25.11	>25
MMV1634440	OSM-S-628	MK110-1b	4.161	2.002	3.082
MMV1634441	OSM-S-629	MK135-1	>25.11	>25.11	>25
MMV1634442	OSM-S-630	MK140-1	>25.11	>25.11	>25
MMV1634443	OSM-S-632	MK117-2	>25.11	>25.11	>25
MMV1634444	OSM-S-633	MK137-1	>25.11	>25.11	>25
MMV1634445	OSM-S-639	MK150-1c	>25.11	>25.11	>25
MMV689970	OSM-S-294	MK113-1a	1.628	1.22	1.42
MMV897698	OSM-S-369	EGT 92-1	0.646	0.423	0.534

• original data plots in my ELN
• data has been entered into the master list

Dundee Assay curves - 2 November 2018.pdf
Dundee Assay curves - 1 November 2018.pdf

[mbhebhe]

ALL results in!

[drc007]

@mbhebhe Are the structures for the SGS-UNC correct? Is sulphur in the wrong place? Compared to https://openlabnotebooks.org/shorter-procedure-to-access-thieno23-dpyrimidines/

[MFernflower]

I wonder if there's any interest in obtaining the boronic acids used to make compounds ap81 and ap193 [most novel of the bunch imo] and coupling them to our aminothienopyrmidine core? ---------- Perhaps the reason the ap compounds were inactive was because of the carboxylic acid functionality preventing cell penetration? @drc007 @mbhebhe Sigma sells the thiophene boronic acid super cheap but I cannot find the acetylpyridine boronic acid https://www.sigmaaldrich.com/catalog/product/aldrich/436836

[mbhebhe]

@drc007 Alfredo sent me the structures and SMILES. I believe the sulfurs are in the correct place. We asked him to send the thieno[3,2-d]pyrimidines and not the thieno[2,3-d]pyrimidines.

@MFernflower out of the two I think our core coupled to the thiophene would be interesting. Within S3, having para substituted phenyls made the drug less potent. But this one is a para substituted heterocycle, so it may be an interesting compound as well.

[mattodd]

Two quick thoughts here:

1. OHOH (OSM-S-556) is decently active. I bet it's better than that. Note that the reference compound OSM-S-369 has surprisingly low potency, and that the difluoro compound OSM-S-560 is oddly low - I'd expect those two OHOH's to be broadly similar.

2. The confirmation of potency for OHOH means the measurement of solubility (should be fine) and clearance (the key) are top priority. We have sample @edwintse @maratsydney ?

[MFernflower]

@mattodd @drc007 since we have confirmation of potency of OHOH compound I have been thinking about something along the lines of this:

[drc007]

@mattodd Difficult to see how to interpret the results. Do you take them at face value? Certainly wrong to cherry pick results that fit hypothesis. Sometimes assays are unreliable and we need to get extra repeats, suspect this is the case here.

[maratsydney]

@mattodd @drc007 for both OHOH compounds we have enough of it for reevaluation assay and metabolic studies.

For the reference compound deviation from 0.25 uM to 0.53 can be explained as a general error of assay, since it has only 8 points for range from 1 nM to 10000 nM. Want to point out that apart from our reference compound I included one more (OSM-S-294) that was tested at other facility (Syngene IC50 = 1.60) and Dundee result came back very close (Dundee IC50 = 1.42) which is definitely good.

[MFernflower]

I do not think this compound ever been evaluated? (shown with potential synthesis route) @mattodd

[mattodd]

Compounds relevant to Series 3 linked on wiki. Are they all in the OSM Master List @mbhebhe ?