Uses
JNJ7777120 is a histamine 4 receptor (H4R) antagonist on CCL17 and CCL22 chemokine production by human monocyte-derived Langerhans cells in patients with atopic dermatitis.
Uses
JNJ7777120 has been used as a histamine-4 receptor antagonist:
- to study its effects on the pro-inflammatory microglia in rats
- to study its effects on the Parkinson′s-like pathology in rat brain
- to study its effects on the histamine receptor interaction in periodontal ligament fibroblasts (PDLF)
Biological Activity
histamine has been reported to play an important role in a large number of physiological processes. jnj-7777120, the first potent and selective non-imidazole histamine h4 receptor antagonist with ki of 4.5 nm, exhibits more than 1000-fold selectivity over the other histamine receptors. [1]
Biochem/physiol Actions
JNJ7777120 may exhibit neuroprotective effects against ischemic brain damage. It acts as an anti-inflammatory agent to treat inflammatory diseases. JNJ7777120 is observed to reduce colonic injury, cytokine production, and neutrophil infiltration.
Synthesis
The general procedure for the synthesis of (5-chloro-1H-indol-2-yl)(4-methylpiperazin-1-yl)methanone from N-methylpiperazine and 5-chloroindole-2-carboxylic acid was as follows: 5-chloroindole-2-carboxylic acid (0.234 g), HATU (0.569 g), HOAT (0.203 g), and N,N-diisopropylethylamine (0.191 mL) were dissolved in DMF (0.6 mL), N-methylpiperazine (0.1 mL) was added, and the reaction was stirred at room temperature for 48 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate and washed sequentially with 1 M hydrochloric acid, saturated sodium bicarbonate solution and brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 3-10% 2M ammonia in methanol solution/dichloromethane) to afford the target product (5-chloro-1H-indol-2-yl)(4-methylpiperazin-1-yl)methanone (0.18 g). The product was characterized by 1H NMR (400 MHz, CDCl3): δ 9.60 (br s, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 1.8 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H), 4.0 (d, J = 1.5 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1.0) 1H), 4.0 (br m, 4H), 2.56 (t, J = 5.1 Hz, 4H), 2.41 (s, 3H). Elemental analysis results (C14H16ClN3O): calculated values C, 60.54; H, 5.81; N, 15.13; measured values C, 59.99; H, 5.94; N, 18.87.
in vitro
it was reported that nj 7777120 bound to the h4 receptor with a remarkably high affinity. it also demonstrated a greater selectivity over other histamine receptor antagonists. moreover, jnj 7777120 selectively targeted to potent h4 rather than 50 other molecular targets. [2]
in vivo
jnj 7777120 showed an oral bioavailability of about 30% in rats and 100% in dogs, with a half-life of around 3 h in both rats and dogs. it was reported to inhibit histamine-induced chemotaxis and calcium influx in mouse bone marrow-derived mast cells. in addition, in mice, jnj 7777120 could suppress the histamine-induced migration of tracheal mast cells from the connective tissue to the epithelium. moreover, jnj 7777120 was demonstrated to notably inhibit neutrophil infiltration in a mouse zymosan-induced peritonitis model. [2]
IC 50
a histamine h4 receptor antagonist with ic50 of 4.5 nm.
References
[1]jablonowski ja, grice ca, chai w, dvorak ca, venable jd, kwok ak, ly ks, wei j, baker sm, desai pj, jiang w, wilson sj, thurmond rl, karlsson l, edwards jp, lovenberg tw and carruthers ni. the first potent and selective non-imidazole human histamine h4 receptor antagonists. j med chem. 2003 sep; 46(19): 3957-60.
[2]thurmond rl, desai pj, dunford pj, fung-leung wp, hofstra cl, jiang w, nguyen s, riley jp, sun s, williams kn, edwards jp and karlsson l. a potent and selective histamine h4 receptor antagonist with anti-inflammatory properties. j pharmacol exp ther. 2004 apr; 309(1): 404-13.
