BACKGROUND AND PURPOSEFostamatinib is an inhibitor of spleen tyrosine kinase (TK). In patients, fostamatinib treatment was associated with increased BP. Some TK inhibitors cause BP elevation, by inhibiting the VEGF receptor 2 (VEGFR2). Here, we have assessed the mechanistic link between fostamatinib-induced BP elevation and inhibition of VEGF signalling. EXPERIMENTAL APPROACHWe used conscious rats with automated blood sampling and radio telemetry and anaesthetized rats to measure cardiovascular changes. Rat isolated aorta and isolated hearts, and human resistance vessels in vitro were also used. NO production by human microvascular endothelial cells was measured with the NO-dependent probe, DAF-FM and VEGFR2 phosphorylation was determined in mouse lung, ex vivo. KEY RESULTSIn conscious rats, fostamatinib dose-dependently increased BP. The time course of the BP effect correlated closely with the plasma concentrations of R406 (the active metabolite of fostamatinib). In anaesthetized rats, infusion of R406 increased BP and decreased femoral arterial conductance. Endothelial function was unaffected, as infusion of R406 did not inhibit hyperaemia-or ACh-induced vasodilatation in rats. R406 did not affect contraction of isolated blood vessels. R406 inhibited VEGF-stimulated NO production from human endothelial cells in vitro, and treatment with R406 inhibited VEGFR2 phosphorylation in vivo. R406 inhibited VEGF-induced hypotension in anaesthetized rats. CONCLUSIONS AND IMPLICATIONSIncreased vascular resistance, secondary to reduced VEGF-induced NO release from endothelium, may contribute to BP increases observed with fostamatanib. This is consistent with the elevated BP induced by other drugs inhibiting VEGF signalling, although the contribution of other mechanisms cannot be excluded. AbbreviationsDABP, diastolic arterial BP; dP/dt +/−, the rate of left ventricle pressure rise and decline; FBF, femoral arterial blood

Translational pharmacokinetic (PK) models are needed to describe and predict drug concentration‐time profiles in lung tissue at the site of action to enable animal‐to‐man translation and prediction of efficacy in humans for inhaled medicines. Current pulmonary PK models are generally descriptive rather than predictive, drug/compound specific, and fail to show successful cross‐species translation. The objective of this work was to develop a robust compartmental modeling approach that captures key features of lung and systemic PK after pulmonary administration of a set of 12 soluble drugs containing single basic, dibasic, or cationic functional groups. The model is shown to allow translation between animal species and predicts drug concentrations in human lungs that correlate with the forced expiratory volume for different classes of bronchodilators. Thus, the pulmonary modeling approach has potential to be a key component in the prediction of human PK, efficacy, and safety for future inhaled medicines.

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure−activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.

While bronchodilators and inhaled corticosteroids are the mainstay of asthma treatment, up to 50% of asthmatics remain uncontrolled. Many studies show that the cysteinyl leukotriene cascade remains highly activated in some asthmatics, even those on high-dose inhaled or oral corticosteroids. Hence, inhibition of the leukotriene C4 synthase (LTC4S) enzyme could provide a new and differentiated core treatment for patients with a highly activated cysteinyl leukotriene cascade. Starting from a screening hit (3), a program to discover oral inhibitors of LTC4S led to (1S,2S)-2-({5-[(5-chloro-2,4-difluorophenyl)­(2-fluoro-2-methylpropyl)­amino]-3-methoxypyrazin-2-yl}­carbonyl)­cyclopropanecarboxylic acid (AZD9898) (36), a picomolar LTC4S inhibitor (IC50 = 0.28 nM) with high lipophilic ligand efficiency (LLE = 8.5), which displays nanomolar potency in cells (peripheral blood mononuclear cell, IC50,free = 6.2 nM) and good in vivo pharmacodynamics in a calcium ionophore-stimulated rat model after oral dosing (in vivo, IC50,free = 34 nM). Compound 36 mitigates the GABA binding, hepatic toxicity signal, and in vivo toxicology findings of an early lead compound 7 with a human dose predicted to be 30 mg once daily.

Fostamatinib is a tyrosine kinase inhibitor with activity against spleen tyrosine kinase which has completed clinical trials for patients with rheumatoid arthritis. In clinical studies fostamatinib treatment was associated with a small elevation of systemic arterial blood pressure (BP), a similar finding to that seen with other kinase inhibitors, especially those that inhibit VEGFR2 signaling. We have investigated the link between fostamatinib-induced blood pressure elevation and plasma levels of the fostamatinib-active metabolite R940406 in conscious rats and found the time course of the BP effect correlated closely with changes in R940406 plasma concentration, indicating a direct pharmacological relationship. Free plasma levels of R940406 produced in these studies (up to 346 nmol/L) span the clinically observed mean peak free plasma concentration of 49 nmol/L. We have demonstrated that the blood pressure elevation induced by fostamatinib dosing can be successfully controlled by a variety of methods, notably simple drug withdrawal or codosing with a range of standard antihypertensive agents such as atenolol, captopril, and nifedipine. These findings support potential methods of maintaining patient safety while on fostamatinib therapy. Furthermore, we have demonstrated, using nifedipine as an example agent, that this blood pressure control was not achieved by reduction in plasma exposure of R940406, suggesting that potential benefits from the pharmacology of the investigational drug can be maintained while blood pressure control is managed by use of standard comedications.