Table 5.
SAR study exploring compounds 65 and 67–74, with IC50 binding data for hCRTH2 of selected compounds, measured in the presence and absence of human serum albumin (HSA) in the assay buffera (values were obtained from [77]).
| Compd. | hCRTH2 Receptor Interaction | Prostanoid Receptor Interaction | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Binding in | Ca2+ Flux a | cAMP | hESC | hDP1 | fSel c | hEP2 | hEP4 | |||
| Buffer IC50 d | HSA IC50 d | fHSA b | IC50 d | IC50 d | IC50 d | Binding IC50 d | β-Arrestin IC50 d | β-Arrestin IC50 d | ||
| Setipiprant | 6 | 340 | 57 | 30 | 80 | 235 | 1290 | 215 | 2600 | >10,000 |
| 65 | 9 | 60 | 6 | 50 | 160 | 130 | >10,000 | >1100 | >10,000 | >10,000 |
| 67 | 4 | 12 | 3 | 40 | 70 | 34 | >10,000 | >2500 | >10,000 | >10,000 |
| 68 | 9 | 60 | 7 | 40 | 95 | 60 | >10,000 | >1100 | >10,000 | >10,000 |
| 69 | 190 | 180 | 1 | 1280 | nd | nd | 4100 | 22 | >10,000 | >10,000 |
| 70 | 11 | 70 | 6 | 20 | 380 | 180 | 2200 | 200 | >10,000 | >10,000 |
| 71 | 70 | 530 | 7 | 660 | nd | nd | 310 | 4.1 | 2700 | >10,000 |
| 72 | 4 | 180 | 45 | 70 | 160 | 275 | >10,000 | >2500 | >10,000 | >10,000 |
| 73 | 5 | 35 | 7 | 15 | 40 | 50 | >10,000 | >2000 | >10,000 | >10,000 |
| 74 | 10 | 30 | 3 | 65 | 160 | 210 | >10,000 | >1000 | 9500 | >10,000 |
nd = not determined.a IC50 values are given for the effects in the cell based Ca2+ flux assay, the cAMP homogeneous time resolved fluorescence (HTRF) assay, and the human eosinophil shape change assay. Data are given to demonstrate selectivity against prostanoid receptors hDP1, hEP1-4, and hTP2. The IC50 values represent the mean from at least three independent experiments if not stated otherwise. b Human serum albumin shift factor fHSA = IC50 (HSA)/IC50 (buffer). c Selectivity factor fSel = IC50 (hDP1)/IC50 (hCRTH2). d Units are nM.