1 This paper describes the effects of GRI17289 (1-[[3-bromo-2-[2-(lH-tetrazol-5-yl)phenyl]-5-benzofuranyl]methyl]-2-butyl-4-chloro-lH-imidazole-5-carboxylic acid) at angiotensin receptors and binding sites in rabbit aorta, rat liver and bovine cerebellum preparations in vitro. 2 In rabbit isolated aortic strips, GRI 17289 (0.3, 1 and 3 nM) caused a concentration-related, insurmountable suppression of the concentration-response curve to angiotensin II (All). When the contact time was increased, a greater degree of antagonism of All was observed, suggesting that GRi17289 is slow to reach equilibrium. A pKB of 9.8±0.1 was calculated for GRI17289 after 3h incubation.GR1 17289 (1 tiM) did not affect contractile responses to phenylephrine or 5-hydroxytryptamine (5-HT) in the rabbit aorta. 3 GRI 17289 (1 nM) alone caused a marked suppression and a slight rightward displacement of the All concentration-response curve. Co-incubation with the competitive, surmountable AT, receptor antagonist, losartan (10 nM, 100 nm and 1 ,LM), resulted in a concentration-related upward and rightward displacement of the concentration-response curve to subsequently administered All. In separate experiments in which preparations were pre-incubated with GR1 17289 (1 nM), subsequent addition of losartan (1 JLM) for 2, 15 or 45 min caused a further, but similar, rightward displacement of the concentration-response curve to subsequently administered All with a time-dependent increase in the maximum response. 4 Suppression of All-induced contractile responses, caused by superfusion with GRI17289 (0.3, 1 or 3 nM) was not reversed by continuously washing the tissues for 3 h; in fact, the potency of GRI 17289 was slightly enhanced after this period.5 In rat liver membranes, GRI17289 was a potent competitor with [3H]-AII for AT, binding sites (pKi = 8.7 ± 0.1) but in bovine cerebellum membranes, it was a very weak competitor for AT2 binding sites (pKi<6). Pre-incubation of rat liver membranes with GRI17289 had little effect on its affinity (pKi = 9.1 ± 0.21), but increasing the concentration of bovine serum albumen in the assay buffer from 0.001% to 0.1% w/v decreased affinity (pKi= 7.5 ± 0.1). 6In saturation binding experiments in rat liver membranes, GRI 17289 (12 nM) increased the Kd of[3H]-AII from 0.28 ± 0.06 nM to 0.37 ± 0.02 nM, and decreased Bm. from 10.0 ± 0.1 to 5.6 ± 0.3 fmol mg' tissue. In other experiments, GR1 17289 (1 jIM) did not alter the rate of dissociation of[3H]-AII from AT1 binding sites, following addition of excess unlabelled All.7 In rabbit aorta vascular smooth muscle membranes, GR1 17289 competed with ['25I]-Sar'1le8 All for binding to AT, binding sites. In the presence of 0.1% w/v bovine serum albumen, a pIC50 of 7.6 ± 0.1 was calculated. Under the same conditions, but with rat liver membranes, a pIC50 of 7.8 ± 0.1 was determined.8 Taken together, these results show that GRI17289 is a potent, specific, selective and insurmountable antagonist at angiotensin AT, receptors. Its profile in the rabbit aorta is consistent with ...

1 The effect of GRI 17289, an angiotensin AT, receptor antagonist, on diastolic blood pressure (DBP) was determined in angiotensin-dependent and angiotensin-independent models of hypertension in rats. In addition, the antagonist profile of GRi 17289 at angiotensin AT1 receptors was determined in conscious renal hypertensive rats and conscious normotensive rats, dogs and marmosets. 2 Intra-arterial and oral administration of GRI17289 (0.3-3mgkg-', i.a.; 1-10mgkg-', p.o.) to 6-day left renal artery ligated hypertensive (RALH) rats (DBP> 140 mmHg) produced significant, dose-related reductions in DBP with little apparent effect on heart rate (< 15%). The antihypertensive effect of GRI 17289 developed progressively over several hours and with some doses persisted for 24-48 h after administration. 3 Administration of GRI17289 (1 mg kg-', i.a.) on 5 consecutive days to RALH rats reduced DBP on each day. The antihypertensive effect of GR1 17289 was not cumulative as DBP had almost returned to base-line values, 24 h after administration of each dose. 4 A dose of GRI 17289 (3 mg kg', i.a.), which produced a substantial reduction in DBP (about 70 mmHg) in RALH rats, was administered to rats in which blood pressure was elevated either by unilateral renal artery clipping, sustained infusion of angiotensin II (All), DOCA-salt administration or genetic inbreeding. GR1 17289 reduced DBP in rats in which the renin-angiotensin system was activated by renal artery clipping or All infusion but had little effect in normotensive rats, DOCA-salt rats and SHR. 5 Systemic administration of All to RALH rats and to normotensive rats, dogs and marmosets elicited reproducible pressor responses in all species. Systemic or oral administration of GR1 17289 (3 mg kg-') inhibited the pressor responses produced by All, resulting in parallel, rightward displacements of All dose-response curves. 6 Maximal displacements of All dose-response curves occurred 1 h and 1-7 h after systemic and oral administration, respectively. GR1 17289 produced a 32-246 fold displacement after systemic administration and a 4-12 fold displacement after oral administration. The effect in dogs was short lasting after systemic administration but the effect of GR I17289 lasted for up to 24 h in rats and marmosets and for up to 24 h after oral administration in all species. The antagonist activity appeared specific for angiotensin receptors as GRi17289 did not inhibit pressor responses to phenylephrine or vasopressin. 7 These experiments demonstrate that GRI 17289 reduces blood pressure in conscious hypertensive rats after both systemic and oral administration, and is an effective antagonist at angiotensin AT, receptors in conscious rats, dogs and marmosets.

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Prostaglandin D2 (PGD2) acting at the CRTH2 receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells) has been linked with a variety of allergic and other inflammatory diseases. We describe a family of indole-1-sulfonyl-3-acetic acids that are potent and selective CRTH2 antagonists that possess good oral bioavailability. The compounds may serve as novel starting points for the development of treatments of inflammatory disease such as asthma, allergic rhinitis, and atopic dermatitis.