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.

The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators (S)-1 and (S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion. Importantly, and in sharp contrast to eplerenone, this was achieved without substantial changes to the urine Na + /K + ratio after acute treatment in rat, which predicts a reduced risk for hyperkalemia. This work led to selection of (S)-1 (AZD9977) as the clinical candidate for treating MR-mediated cardio-renal diseases, including chronic kidney disease and heart failure. On the basis of our findings, we propose an empirical model for prediction of compounds with low risk of affecting the urinary Na + /K + ratio in vivo.

In one of our drug development projects, we identified potent KRASG12C inhibitors for treatment of cancer. For our early preclinical studies, we needed a strategy to enable supply of two candidates in a cost-effective and productive manner. The active pharmaceutical ingredients (APIs) were structurally complex and were initially obtained via long linear sequences resulting in time-consuming manufactures. In addition, both two candidates comprised a biaryl fragment with hindered rotation along the chiral axis. As a result, a pair of stable atropisomers was generated for each candidate. With special attention to the chromatographic challenges for the atropisomer separation and for the API purification, this article describes our initial efforts to develop synthetic routes that were amenable for multigram synthesis of our two drug candidates. In particular, the consequences of implementing a key Suzuki reaction late or early in the sequence are discussed.

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.

We herein describe a method for palladium-catalyzed C−N cross-coupling of aryl amines and aryl halides in a biphasic reaction medium composed of 2methyltetrahydrofuran (MeTHF) and water. By effective solubilization of the inorganic base used, common challenges associated with the scalability of Buchwald− Hartwig aminations using inorganic bases were circumvented. The mildly basic nature of the reaction conditions was highlighted by the facile coupling of a base-sensitive substrate, which could be converted to the corresponding product with a high level of crude purity. The method is operationally simple and displays an improved safety and sustainability profile compared with many alternative strategies for large-scale Buchwald−Hartwig amination. Relying on a commonly available dialkylbiarylphosphine ligand, this approach was applied to three clinically relevant C−N cross-coupling reactions on the hecto-to kilogram scale.

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A linear 14-step sequence was developed for the synthesis of an oxaspirocyclic cyclopentane-based candidate drug 1 containing four chiral centers. Compared with the first-generation synthesis with an overall yield of 0.7%, which also included several chromatographic purifications, the large-scale approach furnished >800 g of API 1 in 19% overall yield, and chromatography was avoided in all but two steps. The major achievements were the development of a Curtius rearrangement where hazards were minimized, a robust and safer dose-controlled allylzinc addition to a ketone, and a selective monohydrolysis of a diester.

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