CN-115916749-B - Alpha-1 antitrypsin modulators

Abstract

Novel compounds, compositions, and methods of use and preparation thereof, which are useful in the treatment of alpha-1 antitrypsin deficiency (AATD).

Inventors

• S. Jilu
• G. S. Fleming
• J.WANG
• J.XU
• K.B. Daniel
• BOYD MICHAEL J.
• M.A. MORRIS
• N.D. Wall
• COLLIER PHILIP N
• S. Kaisavan
• S.M. Rankin
• M.P. CLARK
• H.Deng
• D.M. Boucher
• FANNING LEV TYLER DEWEY
• A B Holzer
• D.J. Hurley
• M. A. Johnson Jr
• J.P. Maxwell
• R.J. Swift
• T. L. Tapley
• S.A. Thomson
• Q.Tang
• V. Damanez
• P. M. nuhant
• P. JONES
• D. Messersmith
• U.K. Bandarag
• K.M. Cottrell
• M.A. Brodney

Assignees

• 弗特克斯药品有限公司

Dates

Publication Date

20260505

Application Date

20210402

Priority Date

20200403

Claims (5)

1. 1. A compound selected from the group consisting of: A tautomer thereof, a deuterated derivative of said compound or of said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
2. 2. A pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1.
3. 3. Use of at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1 for the manufacture of a medicament for the treatment of alpha-1 antitrypsin deficiency in a patient in need thereof.
4. 4. Use of at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to claim 1 for the manufacture of a medicament for modulating alpha-1 antitrypsin (AAT) activity in a patient in need thereof.
5. 5. The use of claim 3 or claim 4, wherein the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is administered in combination with AAT potentiation therapy and/or AAT replacement therapy.

Description

Alpha-1 antitrypsin modulators The present application claims priority from U.S. provisional application No. 63/004,713, filed on even 3, 4/2020, the contents of which are incorporated herein by reference in their entirety. The present disclosure provides compounds capable of modulating alpha-1 antitrypsin (AAT) activity and methods of treating alpha-1 antitrypsin deficiency (AATD) by administration of one or more such compounds. AATD is a genetic disease characterized by low circulating levels of AAT. Although AATD treatment methods exist, there is currently no cure. AAT is produced mainly in hepatocytes and secreted into the blood, but it is also produced by other cell types, including lung epithelial cells and certain leukocytes. AAT inhibits several serine proteases secreted by inflammatory cells (most notably neutrophil elastase [ NE ], protease 3 and cathepsin G), thereby protecting organs such as the lung from protease-induced damage, particularly during inflammation. The most common AATD-related mutations include substitution of lysine for glutamic acid in the SERPINA1 gene encoding AAT protein (E342K). Such mutations are called Z mutations or Z alleles, which result in misfolding of the translated protein and thus are not secreted into the blood and can polymerize within the producer cell. Thus, circulating AAT levels in individuals homozygous for the Z allele (PiZZ) were significantly reduced, with only about 15% of the mutant Z-AAT protein correctly folded and secreted by the cells. Another consequence of the Z mutation is that secreted Z-AAT has reduced activity compared to wild-type protein, 40% to 80% of normal anti-protease activity (American society of thoracic/European respiratory Association, am J RESPIR CRIT CARE Med.2003;168 (7): 818-900; and Ogushi et al J Clin invest.1987;80 (5): 1366-74). Accumulation of polymerized Z-AAT protein within hepatocytes leads to functional acquired cytotoxicity, which can lead to cirrhosis or liver cancer and neonatal liver disease in 12% of patients later in life. This accumulation may spontaneously subside, but is fatal to a small number of children. The lack of circulating AAT results in unregulated protease activity, degrading lung tissue over time, leading to a form of Chronic Obstructive Pulmonary Disease (COPD), i.e., emphysema. This effect is severe in individuals with PiZZ and is often manifested in the middle age, resulting in reduced quality of life and reduced longevity (average 68 years) (Tanash et al Int J Chron Obstruct Pulm Dis.2016; 11:1663-9). The effect was more pronounced in the PiZZ individuals smoking, resulting in a further shortened life span (58 years). (Piitulainen and Tanash, COPD 2015;12 (1): 36-41). Individuals with PiZZ account for the majority of patients with clinically relevant AATD lung disease. Thus, there is a need for additional effective treatments for AATD. Milder forms of AATD are associated with SZ genotypes, where the Z allele binds to the S allele. The S allele is associated with a decrease in circulating AAT levels, but does not cause cytotoxicity of hepatocytes. The result is clinically significant lung disease, not liver disease. (Fregonese and Stolk, orphanet J Rare Dis.2008; 33:16). As with the ZZ genotype, the lack of circulating AAT in SZ genotype subjects results in unregulated protease activity, degradation of lung tissue over time, and can lead to emphysema, particularly in smokers. For AAT-deficient individuals suffering from or exhibiting signs of overt lung or liver disease, the current standard of care is intensive or protein replacement therapy. The boost therapy includes administration of purified human AAT protein concentrate from pooled donor plasma to boost the deleted AAT. Although infusion of plasma proteins has been shown to increase survival or slow down emphysema progression, intensive therapy is often inadequate in challenging conditions, such as during active pulmonary infection. Similarly, while protein replacement therapies have shown promise in slowing disease progression, enhancement therapies do not restore normal physiological regulation of patient AAT and their efficacy is difficult to demonstrate. Furthermore, intensive therapy requires weekly follow-up of treatment and does not address liver disease driven by the toxic function gain of the Z allele. Thus, there is a continuing need for new and more effective AATD treatments. One aspect of the present disclosure provides compounds of formulas (I), (IIa) - (IIc), (III), (IV), (Va) - (Vc), (VIa) - (VIc), and (VIIa) - (VIIe) useful in the treatment of AATD, as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives. For example, a compound of formula (I), a tautomer thereof, deuterated derivatives of these compounds or tautomers, or a pharmaceutically acceptable salt of any of the foregoing may be depi