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RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists
Author(s) -
Bley Keith R,
Bhattacharya Anindya,
Daniels Don V,
Gever Joel,
Jahangir Alam,
O'Yang Counde,
Smith Steven,
Srinivasan Dinesh,
Ford Anthony P D W,
Jett MaryFrances
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706554
Subject(s) - receptor , chemistry , receptor antagonist , prostacyclin , antagonist , pharmacology , stereochemistry , biochemistry , biology
Prostacyclin (PGI 2 ) possesses various physiological functions, including modulation of nociception, inflammation and cardiovascular activity. Elucidation of these functions has been hampered by the absence of selective IP receptor antagonists. Two structurally distinct series of IP receptor antagonists have been developed: 4,5‐dihydro‐1H‐imidazol‐2‐yl)‐[4‐(4‐isopropoxy‐benzyl)‐phenyl]‐amine (RO1138452) and R ‐3‐(4‐fluoro‐phenyl)‐2‐[5‐(4‐fluoro‐phenyl)
‐benzofuran‐2‐ylmethoxycarbonylamino]‐propionic acid (RO3244794). RO1138452 and RO3244794 display high affinity for IP receptors. In human platelets, the receptor affinities (p K i ) were 9.3±0.1 and 7.7±0.03, respectively; in a recombinant IP receptor system, p K i values were 8.7±0.06 and 6.9±0.1, respectively. Functional antagonism of RO1138452 and RO3244794 was studied by measuring inhibition of carbaprostacyclin‐induced cAMP accumulation in CHO‐K1 cells stably expressing the human IP receptor. The antagonist affinities (p K i ) of RO1138452 and RO3244794 were 9.0±0.06 and 8.5±0.11, respectively. Selectivity profiles for RO1138452 and RO3244794 were determined via a panel of receptor binding and enzyme assays. RO1138452 displayed affinity at I 2 (8.3) and PAF (7.9) receptors, while RO3244794 was highly selective for the IP receptor: p K i values for EP 1 (<5), EP 3 (5.38), EP 4 (5.74) and TP (5.09). RO1138452 (1–10 mg kg −1 , i.v.) and RO3244794 (1–30 mg kg −1 , i.v.) significantly reduced acetic acid‐induced abdominal constrictions. RO1138452 (3–100 mg kg −1 , p.o.) and RO3244794 (0.3–30 mg kg −1 , p.o.) significantly reduced carrageenan‐induced mechanical hyperalgesia and edema formation. RO3244794 (1 and 10 mg kg −1 , p.o.) also significantly reduced chronic joint discomfort induced by monoiodoacetate. These data suggest that RO1138452 and RO3244794 are potent and selective antagonists for both human and rat IP receptors and that they possess analgesic and anti‐inflammatory potential.British Journal of Pharmacology (2006) 147 , 335–345. doi: 10.1038/sj.bjp.0706554