Discovery of the Oral Leukotriene C4 Synthase Inhibitor (1S,2S)-2-({5-[(5-Chloro-2,4-difluorophenyl)(2-fluoro-2-methylpropyl)amino]-3-methoxypyrazin-2-yl}carbonyl)cyclopropanecarboxylic Acid (AZD9898) as a New Treatment for Asthma

Abstract

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.

A peculiar dehydration and solid–solid phase transition of the active pharmaceutical ingredient AZD9898 based on in situ single crystal-to-single crystal transformations

“…This material was assigned to have purity more than 99.9% and was used as received. 27 The other chemicals and solvents employed in this study were of analytical grade and used without any purification.…”

“…The single crystal structure of the methanol solvate of AZD9898 (CSD Entry: SIXVIN) has previously been reported in the litterature. 27 In the polymorph screen, a distinctive hydrate phase, Form A hydrate, was isolated from a slurry experiment at room temperature in isopropyl acetate solvent. However, a vapour diffusion technique was used to grow single crystals of AZD9898 Form A using isopropyl acetate as the solvent and n-heptane as the antisolvent.…”

“…1) was previously used as a potential drug candidate and was identified as a picomolar LTC4S enzyme inhibitor with high lipophilic potency. 27 Hydrate crystals of AZD9898 was identified during early development. In this study, we aim to reveal the structural changes during dehydration by using AZD9898 as a model compound to clarify the underlying mechanism of dehydration from the hydrate form to an anhydrous form.…”

Enzymatic synthesis of fluorinated compounds

“…To overcome the poor water solubility and photostability of piperine, a threo -difluoropiperine analog was synthesized and showed higher potency and selectivity than piperine for the treatment of AD (Lizarme-Salas et al 2020 ). Similarly, fluorinated compounds are also the key building blocks of antibiotic, antimalarial, antiinflammatory, asthma, antagonists, migraine, and central nervous system drugs, such as 2,2-bis(6-fluoro-1H-indol-3-yl)ethan-1-amine, fluorinated steroidal, Trifluorothymidine and fluorouracil polytoxin, fluorinated cholesterol, fluorinated galegine, fluorinated bastimolide A, 6(R/S)-fluoropenibruguieramine, fluorinated cyclopropanecarboxylic acid derivatives, aryl-fluoro sulfates, 3-fluoro-4-aminopiperidine, and β-fluoramines (Adler et al 2019 ; Bakhotmah and Abdel-Rahman 2017 ; Campana et al 2020 ; Frank et al 2016 ; Fujino et al 2017 ; Gambini et al 2019 ; Liu et al 2018 ; Molinaro et al 2019 ; Munck Af Rosenschold et al 2019 ; Pupo et al 2019 ; Quintard et al 2018 ; Shao et al 2015 ; Wu et al 2020d ). Accordingly, fluorinated compounds will pay more and more attention to the research and development of new pharmaceutical intermediates.…”

Mechanism-Based Insights into Removing the Mutagenicity of Aromatic Amines by Small Structural Alterations

“…Aromatic amines represent attractive building blocks in drug discovery programs; − therefore, they are often included in the structure of drugs and as such might be released during metabolism. ,,,− Mutagenicity of such fragments or an entire molecule can halt a drug discovery program. ,, Most fragment-sized ArNH 2 (with molecular weight less than 300) are nonmutagenic, − so it should be possible to find close analogues to replace the mutagenic fragment in the drug candidate that retain potency and pharmacokinetic/pharmacodynamic (PK/PD) properties. ,,,− It has been demonstrated that maintaining the desired pharmacological effect is generally more difficult than to eliminate mutagenicity from ArNH 2 fragments with structural alterations . To achieve this successfully, it is important to maintain the chemotype of the ArNH 2 fragment, which is essential for the pharmacology. − Practical guidelines for removing mutagenicity by structural modifications of mutagenic ArNH 2 fragments ,, ought to be versatile and should be based on the physical origin of mutagenicity.…”