Colin Howes

The Identification of Indacaterol as an Ultralong-Acting Inhaled β2-Adrenoceptor Agonist

Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.

Reduction of cardiovascular and thyroxine-suppressing activities of L-T3 by liver targeting with cholic acid

This study was designed to determine whether the conjugation product of L-T3 with cholic acid would result in a liver-targeted compound (CGH 509A) with hypocholesterolemic (HC) activity significantly dissociable from cardiovascular (CV) and thyroxine-suppressing (TS) effects normally observed with thyroid hormone. Evaluation of HC activity in lipemic rats showed that CGH 509A was 6 times less potent than L-T3 with ED25 values estimated at 150 and 25 nmol/kg, respectively. CV function measured as changes in atrial rate, atrial tension and heart weight was determined in euthyroid rats. CGH 509A was at least 64 times less cardio-stimulant than L-T3 with minimum effective doses estimated at 2350 and 37 nmol/kg, respectively. TS activity was assessed in euthyroid rats as the potency of any compound to reduce plasma T4 levels. CGH 509A was 50 times less potent than-L-T3 with ED50 values estimated at 900 and 18 nmol/kg, respectively. From these results, it is clear that, while L-T3 was equally potent on HC, CV and TS activities, the HC potency of CGH 509A was at least 15 and 6 times greater than its CV and TS potencies, respectively.

A novel approach to the site specific delivery of potential HMG-CoA reductase inhibitors

Abstract A novel approach to the site specific delivery of potential HMG-CoA reductase inhibitors based on bile acid uptake is described. The synthesis of inhibitors 9 and 16 was achieved from cholic acid methyl ester. Both compounds 9 and 16 are weak inhibitors of HMG-CoA reductase with IC50 values of 39.2 and 12.3μM respectively. Compound 16 is transported non-specifically across an intestinal epithelial monolayer.