Keith Biggadike

Discovery of GW870086: a potent anti‐inflammatory steroid with a unique pharmacological profile

Glucocorticoids are highly effective therapies for a range of inflammatory diseases. Advances in the understanding of the diverse molecular mechanisms underpinning glucocorticoid action suggest that anti‐inflammatory molecules with reduced side effect liabilities can be discovered. Here we set out to explore whether modification of the 17α position of the steroid nucleus could generate molecules with a unique pharmacological profile and to determine whether such molecules would retain anti‐inflammatory activity.

Fluticasone furoate/fluticasone propionate – different drugs with different properties

The similarity in the names of the recently introduced intranasal glucocorticoid fluticasone furoate (FF; Veramyst®, GlaxoSmithKline/Avamys®, GlaxoSmithKline UK, Uxbridge, UK) and the earlier fluticasone propionate (FP; Flonase®/Flixonase®, GlaxoSmithKline) has led many to assume that the two compounds have the same active principle (fluticasone) (e.g. 1, 2). This has been compounded by FP commonly, and incorrectly, being abbreviated to fluticasone. The purpose of this letter is to highlight that FF and FP are completely different drugs with FF showing distinct and superior properties (3), and hence prevent any misprescription of these drugs in the future. This confusion clearly stems from the unusual assigned glucocorticoid nomenclature which splits these molecules into the steroidal backbone (fluticasone) and the ester substituent (furoate/propionate). This naming convention does suggest that these derivatives could be ester prodrugs of fluticasone. In fact, a number of topical glucocorticoid esters are indeed ester prodrugs releasing the active parent glucocorticoid in the body. However, fluticasone 17α esters are remarkably stable and remain attached to the fluticasone backbone even during metabolism. Their pharmacological activity is mediated by the entire molecule (backbone + ester) and they share no common metabolites (Fig. 1) – neither FF nor FP is metabolised to fluticasone. FF and FP are therefore structurally distinct drug substances with distinct properties. Figure 1 Structures of fluticasone furoate and fluticasone propionate and their major metabolites. The furoate and propionate moieties are far from inert appendages but serve to significantly enhance the glucocorticoid activity of fluticasone, which has never itself been developed. Key interactions of FF with the glucocorticoid receptor have been elucidated by X-ray crystallography which shows the ester derived from 2-furoic acid occupying a discrete pocket on the receptor much more completely than does the smaller propionate ester of FP (4). The resulting enhanced affinity of FF for the target receptor is reflected in the lower daily dose of Veramyst (110 µg) compared with Flonase (200 µg). The ester group also contributes to the physicochemical characteristics of the molecule which impact on solubility, dissolution rate, tissue affinity, and hence pharmacokinetic and pharmacodynamic properties. Thus, the ester derived from 2-furoic acid in FF confers higher affinity for both nasal and lung tissue compared with FP (5, 6) and recent studies with inhaled FF have shown that this translates to enhanced lung residency and once-daily efficacy in asthma (7, 8). There is already some evidence that the characteristics of FF may result in superior symptom reduction compared with FP (9, 10) or similar improvements in symptoms at less frequent dosing schedules (11), which could result in reduced health-care costs/concomitant medication use (12); however, prospective, randomised, head-to-head studies are required to provide a definitive answer. With new inhaled products containing FF in Phase III trials (Relovair®, GlaxoSmithKline) it is important for prescribers to understand that this is a novel glucocorticoid, not to be confused with FP. Moreover, the practice of abbreviating FP and FF to fluticasone should be discouraged.

Structure–activity relationship on human serum paraoxonase (PON1) using substrate analogues and inhibitors

Substrate analogues based on the parent compounds paraoxon and phenyl acetate were tested on human serum paraoxonase (PON1) to explore the active site of the enzyme. Replacement of the nitro group of paraoxon with an amine or hydrogen, as well as electronic changes to the parent compound, converted these analogues into inhibitors. Introduction of either electron-withdrawing or donating groups onto phenyl acetate resulted in reduction in their rate of hydrolysis by PON1.

Effect of the TRPV1 antagonist SB-705498 on the nasal parasympathetic reflex response in the ovalbumin sensitized guinea pig.

Nasal sensory nerves play an important role in symptoms associated with rhinitis triggered by environmental stimuli. Here, we propose that TRPV1 is pivotal in nasal sensory nerve activation and assess the potential of SB‐705498 as an intranasal therapy for rhinitis.

Highly tractable, sub-nanomolar non-steroidal glucocorticoid receptor agonists.

Starting from a non-steroidal glucocorticoid agonist aryl pyrazole derivative, the NFkappaB agonist activity was optimised in an iterative process from pIC(50) 7.5 (for 7), to pIC(50) 10.1 (for 38E1). An explanation for the SAR observed based is presented along with a proposed docking of 38E1 into the active site of the glucocorticoid receptor.

Discovery of a potent series of non-steroidal non α-trifluoromethyl carbinol glucocorticoid receptor agonists with reduced lipophilicity

A novel series of indazole non-steroidal glucocorticoid receptor agonist has been discovered. This series features a sulfonamide central core and meta amides which interact with the extended ligand binding domain. This series has produced some of the most potent and least lipophilic agonists of which we are aware such as 20a (NFκB pIC(50) 8.3 (100%), clogP 1.9). Certain analogues in this series also display evidence for modulated pharmacology.

Novel glucocorticoid antedrugs possessing a 21-(γ-lactone) ring

A series of novel pregnane derivatives bearing γ-butyrolactones at C21 were prepared and tested as glucocorticoid agonists. The compounds were also tested for their lability in human plasma, and found to be rapidly hydrolysed by the enzyme paraoxonase to the respective hydroxyacids.