Rationale Velsecorat (AZD7594) is an inhaled non-steroidal, selective glucocorticoid receptor modulator (SGRM) under development for asthma.Here we describe the results of a Phase 2b study in asthma (NCT03622112).Methods The primary objective was to determine the efficacy of velsecorat (change from baseline (CFB) in trough FEV1 vs placebo (PBO)).A composite endpoint of diary variables capturing clinically relevant deteriorations and severe exacerbations (CompEx) was a key secondary endpoint.This multi-center, parallel-arm, PBO-controlled, double-blind study enrolled adult patients with asthma inadequately controlled following run-in on low-dose budesonide (GINA step 3) to receive velsecorat (50, 90, 180, 360, 720µg), PBO or open-label 100µg fluticasone furoate (FF), once-daily for 12 weeks.Results 805 randomized patients received ≥1 dose and 661 completed the study (only 63% in the PBO group).Velsecorat demonstrated a dose-dependent improvement in CFB trough FEV1 vs PBO over the entire treatment period, but was not significant at week 12 (720 µg LS means difference 0.082L 95%CI -0.003-0.167).For velsecorat 360 & 720 µg vs PBO, sensitivity analysis showed significant differences in overall treatment trough FEV1 CFB Velsecorat 360 & 720 µg significantly delayed time to first CompEx event (HR 0.23&0.20)and reduced CompEx annual event rate (0.60&0.48vsPBO 2.42).Overall, velsecorat was safe and well-tolerated.Conclusions Velsecorat improved lung function and reduced time to first event and annual rate of CompEx events vs PBO.Primary endpoint results were likely influenced by the large proportion of early discontinuations on the PBO arm.

Introduction: Asthma is a chronic inflammatory disease of the airways with typical symptoms manifesting in coughing, wheezing and dyspnoea. Whilst current treatments can be effective, some patients are not properly controlled, and the medications are not ideal and are associated with unwanted side effects. Thus, new therapies are urgently required. Typically, the chronic inflammation endotype is associated with increased levels of type 2 cytokine such as IL-4, IL-5, IL-9 & IL-13. These pro-inflammatory signalling pathways critically depend on Janus Kinase (JAK) I or II signal transduction, therefore the inhibition of JAK pathways represents a promising therapeutic target in asthma. Aims and Objectives: To assess the potential benefit of JAK inhibition using two structurally distinct inhibitors in a in vivo model system. Methods: Two JAK inhibitors, AZD4604 & AZD0449, were intratracheally dosed into sensitised Brown Norway rats one hour prior to aerosolised allergen (OVA) challenge. In one set of animals we assessed target engagement (TE) in the lung tissue by measuring levels of pSTATs. In a parallel set, we measured the Late Asthmatic Response (LAR) and lung inflammation. Results: Administration of both AZD4604 and AZD0449 resulted in dose related reduction of pSTAT3 and pSTAT5, indicating TE in the lung. Furthermore, AZD4604 & AZD0449 administration suppressed LAR and airway inflammation to a similar level to that achieved with the ICS comparator, budesonide. Conclusions: These data indicate that JAK inhibition may be of benefit to patients suffering from allergic asthma.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Background: AZD7594 is a novel, non-steroidal selective modulator of the glucocorticoid receptor, being developed for once-daily treatment of asthma and COPD alone or in combination with a bronchodilator. Aim: To evaluate the safety, tolerability, PK and PD of AZD7594 in healthy Japanese males after inhaled administration of single and multiple doses. Methods: This was a randomized, single-blind, placebo-controlled, sequential-group study. Subjects received AZD7594 via multiple-dose dry powder inhalers (single and repeated doses of 200–1,600 μg delivered once-daily). The PK of AZD7594, plasma cortisol suppression, adverse events, clinical laboratory tests, and physical examinations were assessed. Results: AZD7594 was well tolerated in healthy Japanese males when inhaled as single and multiple doses up to the highest dose level administered 1600 μg. The PK of AZD7594 was characterized with the tmax occurring at 0.25 - 1.5 hours. The systemic exposure of AZD7594 increased in a dose proportional manner with low to moderate variability (12-37%). Steady state was reached on Day 8 with an accumulation ratio of 3.44 to 4.07 for AUC (0-24). Urinary excretion of AZD7594 was minimal (<0.02%). A significant difference between AZD7594 and placebo in cortisol suppression was found only at the 1600 µg dose level, with lower doses (200 and 400 µg) not significantly different than placebo. Conclusion: AZD7594 is well tolerated in healthy Japanese males. The PK of AZD7594 is dose proportional. The plasma cortisol suppression is comparable with all marketed inhaled corticosteroids.

A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment.

N-(5-Bromo-3-methoxypyrazin-2-yl)-5-chlorothiophene-2-sulfonamide 1 was identified as a hit in a CCR4 receptor antagonist high-throughput screen (HTS) of a subset of the AstraZeneca compound bank. As a hit with a lead-like profile, it was an excellent starting point for a CCR4 receptor antagonist program and enabled the rapid progression through the Lead Identification and Lead Optimization phases resulting in the discovery of two bioavailable CCR4 receptor antagonist candidate drugs.

In an industry focused on reducing attrition, lead generation represents a critical stage in drug discovery wherein a considered choice of lead series can significantly reduce the time and resources committed to unpromising chemical series. To aid identification and selection of series with a specific mechanism of action, within property space suitable for the intended mode of administration, many modalities are brought into play and are discussed in this chapter. Aspects covered include the approaches used to find chemical start points, as well as some of the blind alleys that the investigator should avoid, and the need to consider lead-like properties in context of a line-of-sight to the final drug candidate. By way of help, examples are given of both successful and unsuccessful lead generation.

Antagonism of the chemokine receptor CXCR2 has been proposed as a strategy for the treatment of inflammatory diseases such as arthritis, chronic obstructive pulmonary disease and asthma. Earlier series of bicyclic CXCR2 antagonists discovered at AstraZeneca were shown to have low solubility and poor oral bioavailability. In this Letter we describe the design, synthesis and characterisation of a new series of monocyclic CXCR2 antagonists with improved solubility and good pharmacokinetic profiles.

A practical and pragmatic method is demonstrated that aligns lead-like properties with compound diversity for the picking of compounds to synthesise from large virtual libraries. Methods are highlighted for decreasing synthetic attrition through the prior filtration of reagents sets grouped by reaction type. Also disclosed are protocols that use a combination of predicted physicochemical parameters and potential toxicological liabilities to enable the synthesis of lead-like compounds with a low potential risk of exhibiting toxicity or undesirable physicochemical properties. Lastly, a compound-picking process for a 2D compound matrix is demonstrated that maximises the diversity coverage whilst minimising synthetic effort. Thus a very highly optimised process is shown that delivers premium sample quality where lead-likeness and novelty are aligned to afford the best possible enhancement for the corporate compound collection.

Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans.

This review aims to give an overview of current good practice in the prosecution of Lead Generation. It will assess experiences across the field as judged from the contents of the limited number of peer-review disclosures to date. It will also rely heavily on the experiences of the authors from many campaigns within this organisation. Its focus will be on the assembly of an appropriate compound collection for application in High Throughput Screening (HTS), the prosecution of HTS, the profiling of HTS output and, lastly the Hit-to-Lead optimisation of selected HTS output. Excluded from the scope are detailed aspects of library design [1], parallel synthesis [2], virtual library applications [3], virtual screening [4] and fragment screening [5] approaches, all of which have been the subject of recent reviews.

The concepts of 'drug-like' and 'lead-like' chemical properties are having a major influence on the selection of compounds for high-throughput screening, and in the design of lead generation libraries. Medicinal chemists are recycling 'privileged' drug-like structures, whilst aiming to seek optimal physical properties for oral delivery. This approach biases the chemical profiles of compound screening collections towards known structures. Novel library synthesis, creating new chemical classes to address intellectual property, toxicity issues, and less chemically tractable targets, though considered risky, is warranted.: