Targeting COPD: advances on low‐molecular‐weight inhibitors of human neutrophil elastase

Abstract

Chronic obstructive pulmonary disease (COPD) is a major increasing health problem and the World Health Organization (WHO) reports COPD as the fifth leading cause of death worldwide. COPD refers to a condition of inflammation and progressive weakening of the structure of the lung as well as irreversible narrowing of the airways. Current treatment is only palliative and no available drug halts the progression of the disease. Human neutrophil elastase (HNE) is a serine protease, which plays a major role in the COPD inflammatory process. The protease/anti-protease imbalance leads to an excess of extracellular HNE hydrolyzing elastin, the structural protein that confers elasticity to the lung tissue. Although HNE was identified as a therapeutic target for COPD more than 30 years ago, only Sivelestat (ONO-5046), an HNE inhibitor from Ono Pharmaceutical, has been approved for clinical use. Nevertheless, Sivelestat is only approved in Japan and its development in the USA was terminated in 2003. Other inhibitors in pre-clinical or phase I trials were discontinued for various reasons. Hence, there is an urgent need for low-molecular-weight synthetic elastase inhibitors and the present review discusses the recent advances on this field covering acylating agents, transition-state inhibitors, mechanism-based inhibitors, relevant natural products, and major patent disclosures.

Inhibitors and Antibody Fragments as Potential Anti-Inflammatory Therapeutics Targeting Neutrophil Proteinase 3 in Human Disease

“…The tetrahedral structure has been elucidated by X-ray crystallographic studies. Several other substituents, including trifluoromethyl, difluoromethylene, ester, ketone, and a-ketoheterocycles, are transition state analogs (Lucas et al, 2013).…”

“…One advantage of the mechanism-based inhibitors is their good target selectivity due to the presence of a latent electrophilic group, which is unmasked only after protease-induced processing. A variety of templates, including the coumarins, isocoumarins, 2,5-thiadiazolidin-3-one 1, and succinimide, have been used to inhibit serine proteases (Zhong and Groutas, 2004;Lucas et al, 2013).…”

“…The mechanism of this process involves the displacement of a leaving group from the acylating agent. Heterocylic structures including b-lactams, cephalosphorine sulphones, and benzoxazin-4-ones (Teshima et al, 1982;Hedstrom et al, 1984) give extremely stable enzyme-inhibitor complexes that undergo very slow deacylation (Zhong and Groutas, 2004;Lucas et al, 2013). ) (Doherty et al, 1986;Finke et al, 1992).…”

Lipid Peroxide–Mediated Oxidative Rearrangement of the Pyrazinone Carboxamide Core of Neutrophil Elastase Inhibitor AZD9819 in Blood Plasma Samples

“…One such unexpected instability was discovered during the preclinical development of an inhaled drug candidate, 6-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-N-ethyl-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxamide (AZD9819) (Cutting et al, 2011), an inhibitor of human neutrophil elastase for potential treatment of chronic obstructive pulmonary disease (Sjö, 2012;Lucas et al, 2013).…”

Trivaric Acid, a Potent Depside Human Leukocyte Elastase Inhibitor

“…2,3) The imbalance between HLE and its endogenous inhibitors leads to abnormal tissue destruction which is associated with a number of inflammatory diseases including pulmonary emphysema, 4) adult respiratory distress syndrome (ARDS), 5) chronic bronchitis, 6) chronic obstructive pulmonary disease (COPD), 7,8) rheumatoid arthritis (RA), 9) and acute lung injury (ALI). 10) In addition, HLE plays an important role in invasion and metastasis of human breast and lung cancer.…”