Table 3. Activity, Metabolism, PK, and Efficacy of Optimized Lead Compounds from Each Subseries.
| compound | 1 | 4 | 13 | 18 | 27 |
|---|---|---|---|---|---|
| Potencya | |||||
| LE/LLE | 0.3/6.3 | 0.34/4.9 | 0.35/6.0 | 0.31/5.9 | 0.34/7.1 |
| Rat PKb | |||||
| Cl (mL min–1 kg–1) | 15.2 | 4.6 | 3.4 | 19.6 | 14.4 |
| AUC (μM hr) | 1.67 | 6.6 | 8.5 | 1.94 | 0.66 |
| F (%) | 41 | 21 | 85 | 100 | 28 |
| t1/2 (hr) | 1.9 | 1.9 | 1.6 | 2.8 | 0.84 |
| OGTTc | |||||
| % (mg/kg) | –94 (3) | –101 (10) | –65 (10) | –73 (10) | –69 (10) |
| mPPB: Fu (%) | 4.6 | 6.2 | 2.3 | 56 | 31 |
| [3 h]u (μM) | 0.016 | 0.057 | 0.018 | 0.228 | 0.356 |
a
Lipophilic ligand efficiency was calculated using the hSSTR5 biding potency, and logP was determined by HPLC.
b
Rat Sprague; 2 mg/kg PO, 1 mg/kg IV; n = 2.
c
Percent decreased glucose AUC t = 0–120 min compared to vehicle in male C57BL/6 mice fed with high-fat-diet (D12492) for 21 days; compound (mg/kg) dosed 60 min prior to glucose, n = 3. mPPB = mouse plasma free fraction. [3 h]u = free drug 3 h post dose.