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 ...

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Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of human neutrophil elastase (HNE) for the treatment of respiratory disease. These properties made it a suitable candidate for development. Described here is the discovery of three further derivatives of pyrrolidine trans-lactams, which fulfill the criteria required for back-up candidates 28, 29, and 32. These include increased activity in inhibiting HNE in human whole blood (HWB) and comparable pharmacokinetic properties, in particular clearance, in two species. To provide a rapid assessment of clearance, cassette dosing in dog was used. Modern array techniques, including the synthesis of mixtures, were used to synthesize compounds rapidly. Having selected three potential compounds as back-up candidates, they were prepared as single enantiomers and profiled in in vitro and in vivo assays and evaluated pharmacokinetically in rat and dog. These compounds are highly potent and selective HNE inhibitors, with a prolonged pharmacodynamic action. Pharmacokinetically, these compounds are comparable with 1 while they are more potent in HWB. Compound 28, however, has a higher clearance. One of these compounds, 32, was cocrystallized with HNE, and features of this structure are described and compared with the cocrystal structure of 1 in porcine pancreatic elastase.

We have identified GR138950, a potent antagonist of the angiotensin II receptor with high oral bioavailability, as our second drug candidate to GR117289. Using GR117289, a compound with moderate bioavailability (20%) in man as a lead, we pursued a strategy aimed at enhancing bioavailability. The strategy was based on SAR established around the diacid GR117289, and from this, it was proposed that a monoacid, in particular a trifluoromethanesulfonamide, should be better absorbed after oral administration and have enhanced oral bioavailability. This led to the identification of GR138950, a potent antihypertensive agent in the renal hypertensive rat, causing sustained falls in blood pressure after oral administration. Oral bioavailability of GR138950 in rats and dogs is high, confirming that GR138950 is well absorbed after oral administration. Moreover, the low plasma clearance and long plasma half-life suggest that this compound will be suitable for once a day administration. Furthermore, the preliminary data indicate that the high bioavailability of GR138950 seen in rats and dogs translates to man. These results demonstrate clearly that GR138950 has the potential to be a clinically effective antihypertensive agent. Further studies are in progress to evaluate GR138950 in the treatment of hypertension.