C20H27N5O3S (M = 417) yield 83.0 %; (13C δ in ppm; CDCl3, 600 MHz); 172.98; 159.67; 148.27; 140.43; 138.48; 126.87; 123.71; 120.51; 56.42; 51.56; 45.48; 39.81; 32.76; 26.22; 20.51; 13.32; TLC (dichloromethane: methanol: 10:1) Rf = 0.43. IR (for dihydrobromide monohydrate; KBr) cm−1: 3451, 3039, 2968, 2934, 2903, 2784, 2696, 2601, 2515, 2457, 1625, 1599, 1524, GDC-0941 ic50 1445, 1429, 1404, 1353, 1290, 1260, 1176, 1095, 1033, 1009, 968, 870, 742, 725. MS m/z (relative intensity) 417 (M+, 26), 319 (55), 237 (20), 224 (100), 152 (27), 150 (39) 141

(21), 139 (34),120 (25), 112 (29), 111 (68), 98 (88). Elemental analysis for dihydrobromide monohydrate C20H29Br2N5O3S H2O (M = 597.39) Calculated 40.20 % 5.23 % 11.72 % Found 40.46 % 5.03 %

11.77 % mpdihydrobromide 195–197 °C Pharmacology All compounds were tested for H3 antagonistic effects in vitro on the guinea-pig jejunum using standard methods (Vollinga et al., 1992). Male guinea pigs weighing 300–400 g were killed by a blow on the head. A portion of the small intestine, 20–50 cm proximal to the ileocaecal valve (jejunum), was removed and placed in Krebs buffer (composition (mM) NaCl 118; KCl 5.6; MgSO4 1.18; CaCl2 2.5; NaH2PO4 1.28; NaHCO3 25; glucose 5.5 and indomethacin (1 × 10−6 mol/L)). Whole jejunum I-BET-762 cell line segments (2 cm) were prepared and mounted between two platinum electrodes (4 mm apart) in 20 mL Krebs buffer, continuously gassed with 95 % O2:5 % CO2 and maintained at 37 °C. Contractions were recorded isotonically under 1.0 g tension with Hugo Sachs Hebel–Messvorsatz Glutamate dehydrogenase (Tl-2)/HF-modem (Hugo Sachs Electronik, Hugstetten, Germany) connected to a pen recorder. After equilibration for 1 h with AZD9291 solubility dmso every 10 min washings, the muscle segments were stimulated maximally between 15 and 20 V and continuously at a frequency of 0.1 Hz and a duration of 0.5 ms, with rectangular-wave electrical pulses, delivered by a Grass Stimulator S-88 (Grass Instruments

Co., Quincy, USA). After 30 min of stimulation, 5 min before adding (R)-α-methylhistamine, pyrilamine (1 × 10−5 mol/L concentration in organ bath) was added, and then cumulative concentration–response curves (half-log increments) of (R)-α-methylhistamine, H3-agonist were recorded until no further change in response was found. Five minutes before adding the tested compounds, the pyrilamine (1 × 10−5 mol/L concentration in organ bath) was added, and after 20 min cumulative concentration–response curves (half-log increments) of (R)-α-methylhistamine, H3-agonist, were recorded until no further change in response was found. Statistical analysis was carried out with the Students’ t test. In all tests, p < 0.05 was considered statistically significant. The potency of an antagonist is expressed by its pA2 value calculated from the Schild (Arunlakshana and Schild, 1959) regression analysis where at least three concentrations were used. The pA2 values were compared with the potency of thioperamide.