Barry Clive Ross

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‐benzofuranyl]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 μm) 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 μm), 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 μm) 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 AII‐induced contractile responses, caused by superfusion with GR117289 (0.3, 1 or 3 nm) was not reversed by continuously washing the tissues for 3 h; in fact, the potency of GR117289 was slightly enhanced after this period. 5 In rat liver membranes, GR117289 was a potent competitor with [3H]‐AII for AT1 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 GR117289 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, GR117289 (12 nm) increased the Kd of [3H]‐AII from 0.28 ± 0.06 nm to 0.37 ± 0.02 nm, and decreased Bmax from 10.0 ± 0.1 to 5.6 ± 0.3 fmol mg−1 tissue. In other experiments, GR117289 (1 μm) did not alter the rate of dissociation of [3H]‐AII from AT1 binding sites, following addition of excess unlabelled AII. 7 In rabbit aorta vascular smooth muscle membranes, GR117289 competed with [125I]‐Sar1Ile8 AII for binding to AT1 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 GR117289 is a potent, specific, selective and insurmountable antagonist at angiotensin AT1 receptors. Its profile in the rabbit aorta is consistent with the proposal that GR117289 is a slowly reversible (pseudo‐irreversible) antagonist at these receptors.

A CONVENIENT STRATEGY FOR REPLACEMENT OF THE ANOMERIC HYDROXYL GROUP BY DIFLUOROMETHYL FUNCTIONALITY IN CARBOHYDRATE-DERIVATIVES

A series of carbohydrate gem-difluoroenol ethers are readily prepared by the reaction of the corresponding lactones with dibromodifluoromethane, tris(dimethylamino)phosphine and zinc. Subsequent catalytic hydrogenation provides difluoromethyl C-glycoside analogues in which the exocyclic oxygen atom has been replaced by a difluoromethylene unit.

Bromobenzofurans : a new class of potent, non-peptide antagonists of angiotensin II

This paper describes the synthesis and pharmacology of a novel series of benzofurans which are antagonists of angiotensin II. One of these, the bromobenzofuran 11b, is a potent (apparent pKB=9.8) and specific antagonist of angiotensin II which, after oral administration (10mg/Kg), causes marked and long-lasting ( > 24h) falls in blood pressure in renal hypertensive rats.

Structurally simplified squalestatins: A convenient route to a 67-unsubstituted derivative

Abstract The squalestatin 1 , has been converted into the 6,7-unsubstituted analogue, 3 , via inversion of the alcohol at C7, selective removal of the α,β-unsaturated ester at C6 followed by a Corey-Hopkins deoxygenation of the generated 6 R ,7 S -diol.

The squalestatins: C-3 Decarboxylation studies and rearrangement to the 6,8-dioxabicyclo[3.2.1]octane ring system

3-Decarboxy squalestatins 3 and 4 were synthesised via photolysis of t-butyl peroxyester 7. Lactol 10 was isolated unexpectedly from both HCl-dioxan cleavage of 8, a by-product of the photolysis, and attempted Barton decarboxylation of 6. In TFA under anhydrous conditions, 8 was converted to the tricyclic ether 11.

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.

Synthesis of 2-methoxy- and 2-phenoxypenems

Abstract The 2-methoxy- and the novel 2-phenoxypenems 1b and 1a were synthesised from the corresponding 4-allylsulphinylazetidinones 2b , 2a by thermolysis in the presence of triphenylphosphine.

Synthesis of 1,2,4,6-thiatriazine 1,1-dioxides. Part III

Abstract Novel 1,2,4,6-thiatriazine 1, 1-dioxides substituted at either the 2 or 4 ring nitrogen atom have been prepared by cyclizing sulfamido-iso(thio)urea derivatives.

Synthesis of a 7-oxo-1,4-diazabicyclo[3.2.0]hept-3-ene-2-carboxylate (Δ1-azapenem) and a related 3,7-dioxo-1,4-diazabicyclo[3.2.0]heptane-2-carboxylate, a fused β,γ-lactam

The Δ1-azapenem (3) is synthesised by cyclisation of the azetidinone isothiocyanate (7) followed by S-alkylation; the intermediate 7-oxo-3-thioxo-1,4-diazabicyclo[3.2.0]heptane-2-carboxylate (8) can be oxidised by benzeneseleninic anhydride to give a fused β,γ-lactam.

Benzofuran based angiotensin II antagonists related to GR117289: Part III; GR138950, a triflamide with high oral bioavailability.☆

Abstract The identification of GR138950, a non-peptide antagonist of angiotensin II with high oral bioavailability, is described. GR138950 is a potent and selective AT 1 receptor antagonist which causes marked falls in blood pressure in renal hypertensive rats after either systemic or oral administration. It has high bioavailability in both rats and dogs and been selected as our second candidate for clinical development.