David Bryan Yates

Pharmacology of flosequinan

Flosequinan is a novel quinolone with cardiovascular activity that is likely to be of value in the treatment of both heart failure and hypertension. Data generated from animal studies indicate that flosequinan produces dilatation in both veins and arteries, with little associated reflex tachycardia. The compound shows some positive inotropic effects, but the potency is very species dependent. The mode of action of flosequinan seems to involve intracellular calcium handling.

Cardiovascular effects of the novel arteriovenous dilator agent, flosequinan in conscious dogs and cats

1 Flosequinan (BTS 49 465, 7‐fluoro‐l‐methyl‐3‐methylsulphinyl‐4‐quinolone) a novel arteriovenous dilator agent was orally effective in conscious renal hypertensive dogs and normotensive cats. The hypotensive potency of flosequinan was approximately ten times less than that of hydralazine in renal hypertensive dogs, 10 mg kg−1 and 20 mg kg−1 flosequinan causing similar falls in mean blood pressure to 1 mg kg−1 and 3 mg kg−1 hydralazine respectively. In normotensive cats, 5 mg kg−1 flosequinan caused similar falls to 0.5 and l.0 mg kg−1 hydralazine. The onset of hypotensive effect after flosequinan appeared to be slightly slower than after hydralazine in the dog and slightly faster than hydralazine in the cat. 2 The degree of tachycardia and increase in plasma renin activity (PRA) for equivalent falls in mean blood pressure in both species was significantly less for flosequinan than for hydralazine (P < 0.05). 3 In normotensive dogs, flosequinan, 10 and 20 mg kg−1 orally, caused a small but non‐significant increase in sodium and chloride excretion and had little effect on urine volume whereas hydralazine, 1 and 3 mg kg−1 orally, caused a marked retention of sodium and chloride ions and a reduction in urine volume (P < 0.01). 4 Neither flosequinan, 10 mg kg−1 orally, nor hydralazine 1 mg kg−1 orally, affected either glomerular filtration rate measured as creatinine clearance or effective renal plasma flow measured as p‐aminohippuric acid clearance in normotensive dogs. 5 The lesser degree of tachycardia and increase in plasma renin activity together with a lack of sodium retaining activity associated with flosequinan suggest that this agent may have potential advantages over existing therapy as an antihypertensive in man.

4-quinolones as potential cardiovascular agents.

Publisher Summary This chapter focuses on 4-Quinolones as potential cardiovascular agents. Cardiovascular diseases continue to be the focus of considerable attention from the pharmaceutical industry. Prevalence of the disease is high in Western society and, despite publicity surrounding healthier lifestyles, is likely to continue to be a problem. The promising profile of activity shown by certain 4-quinolone-3-sulphoxides, including, in animal models established the true lead potential of 4-quinolone analogues and prompted a major research effort to find other related compounds with potential for development. The strategy for the next phase of the work involved the synthesis of 4-quinolone analogues bearing as 3-substituents groups whose size approximated to those already described above. As physico-chemical parameters were not available for other groups of interest, it was decided to investigate bridged versions of previously identified 3-substituents. The dose-response relationship for antihypertensive effects in renal hypertensive dogs for a range of 4-quinolones is shown in the chapter. Certain 4-quinolones have been shown to possess antihypertensive or hypotensive activity in SH rats, RH dogs and normotensive cats.

Investigation of the effects of BTS 67 582, a novel antidiabetic agent, in the beagle dog

BTS 67 582 stimulates insulin release and causes dose‐dependent glucose‐lowering activity in the conscious beagle dog. Plasma glucose levels were lowered within 1 h and were maximally reduced by 53.2± 2.7% 2–3 h after oral dosing with 90 μmol/kg BTS 67 582 (equivalent to 22.5 mg/kg as the free base). A dose of BTS 67 582 causing a 25% (ED25) reduction of plasma glucose was calculated as 24.7 μmol/kg. No effect on the urinary excretion of glucose was observed (except for a marginal increase at the highest dose tested, 90 μmol/kg BTS 67 582). Insulin‐stimulated glucose disposal is, therefore, the most likely cause of the glucose‐lowering effect of BTS 67 582. BTS 67 582 significantly increased urine flow by 1.9‐ and 2.2‐fold and sodium excretion by 2.8‐ and 2.9‐fold by BTS 67 582 at 30 and 90 μmol/kg, respectively, without increased potassium excretion. In separate studies, increases in the urinary clearance of both creatinine and p‐aminohippuric acid were observed with BTS 67 582 at 90 μmol/kg, indicating that changes in glomerular filtration rate and renal blood flow, respectively, may have contributed to this diuretic effect. BTS 67 582 had no effect on blood pressure or heart rate. In conclusion, in the conscious beagle dog BTS 67 582 stimulates insulin secretion, causes dose‐dependent lowering in plasma glucose, and also possesses mild eukalemic diuretic properties. Drug Dev. Res. 47:137–143, 1999.