In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally.

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.

The in vitro metabolic stability assays are indispensable for screening the metabolic liability of new chemical entities (NCEs) in drug discovery. Intrinsic clearance (CL(int)) values from liver microsomes and/or hepatocytes are frequently used to assess metabolic stability as well as to quantitatively predict in vivo hepatic plasma clearance (CL(H)). An often used approximation is the so called well-stirred model which has gained widespread use. The applications of the well-stirred model are typically dependent on several measured parameters and hence with potential for error-propagation. Despite widespread use, it was recently suggested that the well-stirred model in some circumstances has been misused for in vitro in vivo extrapolation (IVIVE). In this work, we follow up that discussion and present a retrospective analysis of IVIVE for hepatic clearance prediction from in vitro metabolic stability data. We focus on the impact of input parameters on the well stirred model; in particular comparing "reference model" (with all experimentally determined values as input parameters) versus simplified models (with incomplete input parameters in the models). Based on a systematic comparative analysis and model comparison using datasets of diverse drug-like compounds and NCEs from rat and human, we conclude that simplified models, disregarding binding data, may be sufficiently good for IVIVE evaluation and compound ranking at early stage for cost-effective screening. Factors that can influence prediction accuracy are discussed, including in vitro intrinsic clearance (CL(int)) and in vivo CL(int) scaling factor used, non-specific binding to microsomes (fu(m)), blood to plasma ratio (C(B)/C(P)) and in particular fraction unbound in plasma (fu). In particular, the fu discrepancies between literature data and in-house values and between two different compound concentrations 1 and 10 µM are exemplified and its potential impact on prediction performance is demonstrated using a simulation example.

This open-label, single-period study describes the human absorption, distribution, metabolism, excretion, and pharmacokinetics of velsecorat (AZD7594). Healthy subjects received inhaled velsecorat (non-radiolabeled; 720 mg) followed by intravenous infusion of carbon 14 ( 14 C)-velsecorat (30 mg). Plasma, urine, and feces were collected up to 168 hours post-dose. Objectives included identification and quantification of velsecorat and its metabolites (i.e., drug-related material) in plasma and excreta, and determining the elimination pathways of velsecorat by measuring the rate and route of excretion, plasma half-life (t 1/2 ), clearance, volume of distribution and mean recovery of radioactivity. On average, 76.0% of administered 14 C dose was recovered by the end of the sampling period (urine 5 24.4%; feces 5 51.6%), with no unchanged compound recovered in excreta, suggesting that biliary excretion is the main elimination route. Compared with intravenous 14 C-velsecorat, inhaled velsecorat had a longer t 1/2 (27 versus 2 hours), confirming that plasma elimination is absorption-rate-limited from the lungs. Following intravenous administration, t 1/2 of 14 C-drug-related material was longer than for unchanged velsecorat, and 20% of the 14 C plasma content was related to unchanged velsecorat. The geometric mean plasma clearance of velsecorat was high (70.7 l/h) and the geometric mean volume of distribution at steady state was 113 l. Velsecorat was substantially metabolized via O-dealkylation of the indazole ether followed by sulfate conjugation, forming the M1 metabolite, the major metabolite in plasma. There were 15 minor metabolites. Velsecorat was well tolerated, and these results support the progression of velsecorat to phase 3 studies. SIGNIFICANCE STATEMENTThis study describes the human pharmacokinetics and metabolism of velsecorat, a selective glucocorticoid receptor modulator, evaluated via co-administration of a radiolabeled intravenous microtracer dose and a non-radiolabeled inhaled dose. This study provides a comprehensive assessment of the disposition of velsecorat in humans. It also highlights a number of complexities associated with determining human absorption, distribution, metabolism, and excretion for velsecorat, related to the inhaled route, the high metabolic clearance, sequential metabolite formation and the low intravenous dose.

The mitogen‐activated protein kinase p38α pathway has been an attractive target for the treatment of inflammatory conditions such as rheumatoid arthritis. While a number of p38α inhibitors have been taken to the clinic, they have been limited by their efficacy and toxicological profile. A lead identification program was initiated to selectively target prevention of activation (PoA) of mitogen‐activated protein kinase‐activated protein kinase 2 (MK2) rather than mitogen‐ and stress‐activated protein kinase 1 (MSK1), both immediate downstream substrates of p38α, to improve the efficacy/safety profile over direct p38α inhibition. Starting with a series of pyrazole amide PoA MK2 inhibitor leads, and guided by structural chemistry and rational design, a highly selective imidazole 9 (2‐(3′‐(2‐amino‐2‐oxoethyl)‐[1,1′‐biphenyl]‐3‐yl)‐N‐(5‐(N,N‐dimethylsulfamoyl)‐2‐methylphenyl)‐1‐propyl‐1H‐imidazole‐5‐carboxamide) and the orally bioavailable imidazole 18 (3‐methyl‐N‐(2‐methyl‐5‐sulfamoylphenyl)‐2‐(o‐tolyl)imidazole‐4‐carboxamide) were discovered. The PoA concept was further evaluated by protein immunoblotting, which showed that the optimized PoA MK2 compounds, despite their biochemical selectivity against MSK1 phosphorylation, behaved similarly to p38 inhibitors in cellular signaling. This study highlights the importance of selective tool compounds in untangling complex signaling pathways, and although 9 and 18 were not differentiated from p38α inhibitors in a cellular context, they are still useful tools for further research directed to understand the role of MK2 in the p38α signaling pathway.

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The Front Cover shows pillars of drug discovery projects and key questions to ask to avoid getting “lost in translation”. Each project needs a) a hypothesis that modulating protein X could benefit disease Y, b) a design strategy to make leads modulating protein X, and c) a translational screening cascade linking the target and hypothesis. Following structure–activity through the cascade is critical to validate or challenge the project hypothesis. In this case, potent p38 inhibitors were designed to show differential activity on kinases MK2 and MSK1, but this did not translate into preservation of pro‐resolution IL‐10 while inhibiting pro‐inflammatory TNF‐α, contrary to the project hypothesis. More information can be found in the Full Paper by Katerina Pardali, Mickael Mogemark et al. on page 1701 in Issue 19, 2019 (DOI: 10.1002/cmdc.201900303).