The discovery of a potent, intracellular, orally bioavailable, long duration inhibitor of human neutrophil elastase--GW311616A a development candidate.

The discovery of a potent intracellular inhibitor of human neutrophil elastase which is orally active and has a long duration of action is described. The pharmacodynamic and pharmacokinetic properties of a trans-lactam development candidate, GW311616A, are described.

Intracellular inhibition of human neutrophil elastase by orally active pyrrolidine-trans-lactams.

Described are the acylation binding of trans-lactam 1 to porcine pancreatic elastase, the selection of the SO2Me activating group for the lactam N which also confers metabolic stability in hamster liver microsomes, the introduction of aqueous solubility through the piperidine salt 9, the in vivo oral activity of 9 and its bioavailability, and the introduction of 9 as an intracellular neutrophil elastase inhibitor.

5,5-trans lactone-containing inhibitors of serine proteases: identification of a novel, acylating thrombin inhibitor.

Synthesis of a variety of 5,5-trans fused lactones, related to compounds found in extracts of Lantana camara, has provided a series of novel acylating inhibitors of human thrombin, trypsin, chymotrypsin and human leucocyte elastase. The most effective thrombin inhibitor is 7 with an IC50 of 130 nM and a Kobs/[1] of 4,000 M-1 s-1.

Bromobenzofuran-based non-peptide antagonists of angiotensin II: GR138950, a potent antihypertensive agent with high oral bioavailability.

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.

Pharmacological profile of GR117289 in vitro: a novel, potent and specific non-peptide angiotensin AT1 receptor antagonist.

1. This paper describes the effects of GR117289 (1-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-5-benzo-furanyl]methyl ]-2-butyl-4-chloro-1H-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, GR117289 (0.3, 1 and 3 nM) caused a concentration-related, insurmountable suppression of the concentration-response curve to angiotensin II (AII). When the contact time was increased, a greater degree of antagonism of AII was observed, suggesting that GR117289 is slow to reach equilibrium. A pKB of 9.8 +/- 0.1 was calculated for GR117289 after 3 h incubation. GR117289 (1 microM) did not affect contractile responses to phenylephrine or 5-hydroxytryptamine (5-HT) in the rabbit aorta. 3. GR117289 (1 nM) alone caused a marked suppression and a slight rightward displacement of the AII concentration-response curve. Co-incubation with the competitive, surmountable AT1 receptor antagonist, losartan (10 nM, 100 nM and 1 microM), resulted in a concentration-related upward and rightward displacement of the concentration-response curve to subsequently administered AII. In separate experiments in which preparations were pre-incubated with GR117289 (1 nM), subsequent addition of losartan (1 microM) for 2, 15 or 45 min caused a further, but similar, rightward displacement of the concentration-response curve to subsequently administered AII 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).6. In 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 the proposalthat GRI17289 is a slowly reversible (pseudo-irreversible) antagonist at these receptors.