ABSTRACT
In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma.
Subject(s)
Adrenal Cortex Hormones/chemical synthesis , Adrenal Cortex Hormones/pharmacokinetics , Anti-Asthmatic Agents/chemical synthesis , Anti-Asthmatic Agents/pharmacokinetics , Asthma/drug therapy , Drug Design , Administration, Inhalation , Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/pharmacology , Adrenergic beta-Agonists/administration & dosage , Adrenergic beta-Agonists/therapeutic use , Androstadienes/chemistry , Androstadienes/pharmacology , Animals , Anti-Asthmatic Agents/administration & dosage , Anti-Asthmatic Agents/pharmacology , Asthma/epidemiology , Asthma/physiopathology , Delayed-Action Preparations , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Drug Therapy, Combination , Dry Powder Inhalers , Fluticasone , Hepatocytes , Humans , Liver , Lung , Microsomes, Liver , Neutrophils/metabolism , Randomized Controlled Trials as Topic , Rats , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/bloodABSTRACT
Binding and functional affinities of the muscarinic acetylcholine (mACh) receptor antagonists darifenacin, tolterodine, oxybutynin, and atropine were assessed in Chinese hamster ovary (CHO) cells expressing the human recombinant M2 (CHO-m2) or M3 (CHO-m3) receptors, and in guinea pig bladder and submandibular gland. In [N-methyl-3H]scopolamine methyl chloride binding studies in CHO cells, darifenacin displayed selectivity (14.8-fold) for the M3 versus M2 mACh receptor subtype. Oxybutynin was nonselective, whereas atropine and tolterodine were weakly M2-selective (5.1- and 6.6-fold, respectively). Antagonist functional affinity estimates were determined by the inhibition of agonist-induced [3H]inositol phosphate accumulation in CHO-m3 cells and antagonism of the agonist-induced inhibition of forskolin-stimulated cyclic AMP accumulation in CHO-m2 cells. Darifenacin was the most M3-selective antagonist (32.4-fold), whereas oxybutynin, atropine, and tolterodine exhibited lesser selectivity. Functional affinity estimates in guinea pig urinary bladder and submandibular salivary gland using indices of phosphoinositide turnover revealed that oxybutynin, darifenacin, and tolterodine each displayed selectivity for the response in the bladder, relative to that seen in the submandibular gland (9.3-, 7.9-, and 7.4-fold, respectively). In contrast, atropine displayed a similar affinity in both tissues. These data demonstrate that in bladder, compared with submandibular gland from a single species, the mACh receptor antagonists darifenacin, tolterodine, and oxybutynin display selectivity to inhibit agonist-mediated phosphoinositide responses. It is proposed that both responses are mediated via M3 mACh receptor activation and that differential functional affinities displayed by some, but not all, antagonists are indicative of the influence of cell background upon the pharmacology of the M3 mACh receptor.
