US-12624008-B2 - 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoic acid as an inducer of Z A1AT secretion for treating AATD

Abstract

The invention relates to 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoic acid, compositions thereof, and uses of either, for example in the treatment of α 1 -antitrypsin deficiency (A1AD or AATD).

Inventors

• Nigel Ramsden
• David John Fox
• James Andrew Huntington

Assignees

• CENTESSA PHARMACEUTICALS (UK) LIMITED

Dates

Publication Date

20260512

Application Date

20221215

Priority Date

20200615

Claims (4)

1. 1 . A method of treating α 1 -antitrypsin deficiency (AATD) in a subject in need thereof, the method comprising administering to the subject in need thereof a compound represented by the structure of or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound represented by the structure of or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
2. 2 . The method of claim 1 , wherein the administering to the subject in need thereof induces Z α 1 -Antitrypsin (A1AT) secretion in the subject.
3. 3 . The method of claim 1 , wherein the administering to the subject in need thereof increases levels of Z α 1 -Antitrypsin (A1AT) in the subject.
4. 4 . The method of claim 1 , wherein the administering to the subject in need thereof is conducted orally.

Description

CROSS REFERENCE This application is a continuation of International Application No. PCT/GB2021/051496, filed Jun. 15, 2021, which is incorporated herein by reference in its entirety. SUMMARY OF THE DISCLOSURE The invention relates to a composition comprising 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoic acid, uses thereof and uses of 4-((6-oxopyrimidin-1(6H)-yl)methyl)benzoic acid. α1-Antitrypsin (A1AT) is a member of the serpin superfamily produced by the liver and secreted into the blood. It inhibits a variety of serine proteases, especially neutrophil elastase. When blood levels of A1AT are low, excessive neutrophil elastase activity degrades lung tissue resulting in respiratory complications such as chronic obstructive pulmonary disease (COPD). The reference range of A1AT in blood is 0.9-2.3 g/L. Levels lower than this are typical of α1-antitrypsin deficiency (A1AD or AATD), a genetic disorder caused by mutations in the SERPINA1 gene, coding for A1AT. The Z mutation, the most common cause of AATD, is the substitution of glutamate to lysine at position 366 of A1AT (UniProtKB-P01009 (A1AT_HUMAN)), corresponding to position 342 in the mature protein (Z A1AT). The Z mutation affects the folding of AAT resulting in only a small fraction acquiring the native/active state. The remainder is either cleared as misfolded protein or accumulates in the liver as stable polymers. As a consequence of the misfolding, homozygous carriers of the Z mutation (ZZ) have plasma levels of A1AT that are 10-15% of normal, predisposing carriers to COPD. Accumulation of Z A1AT polymers in liver cells predisposes carriers to cirrhosis, liver cancer and other liver pathologies. The current treatment for the lung manifestation of AATD involves augmentation therapy using A1AT concentrates prepared from the plasma of blood donors. The US FDA has approved the use of four A1AT products: Prolastin, Zemaira, Glassia, and Aralast. Dosing is via once weekly intravenous infusion. Augmentation therapy has been demonstrated to slow progression of COPD. The liver manifestations of AATD (e.g. cirrhosis and cancer) are treated with steroids and liver transplantation. Investigational approaches to improved treatment of the liver manifestations include inhibition of Z A1AT polymerisation and increased clearance of polymers through the activation of autophagy. Investigational approaches to improved treatment of both the lung and the liver manifestations are directed towards improvement of Z A1AT folding and secretion. Elliott et al (Protein Science, 2000, 9, 1274-1281) have described an X-ray crystal structure of A1AT and identified five cavities that are potential targets for rational drug design to develop agents that will affect Z A1AT polymerisation. Parfrey et al (J. Biol. Chem., 2003, 278, 35, 33060-33066) have further defined a single cavity that is a potential target for rational drug design to develop agents that will affect Z A1AT polymerisation. Knaupp et al (J. Mol. Biol., 2010, 396, 375-383) have shown that bis-ANS (4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonate) is able to bind to Z A1AT, but not to wild-type A1AT (M A1AT), with 1:1 stoichiometry and a Kd of 700 nM. Chang et al (J. Cell. Mol. Med., 2009, 13, 8B, 2304-2316) have reported a series of peptides, including Ac-TTAI-NH2, that inhibit Z A1AT polymerization. Burrows et al (Proc. Nat. Acad. Sci., 2000, 97, 4, 1796-1801) have shown that a series of non-selective chaperones, including 4-phenylbutyric acid, glycerol and trimethylamine oxide, are able to increase Z A1AT levels in cell supernatants and mouse models. Bouchecareilh et al (Journal of Biological Chemistry, 2012, 287, 45, 38265-38278) describe the use of histone deacetylase inhibitors, in particular SAHA (suberoylanilide hydroxamic acid) to increase the secretion of both wild-type (M A1AT) and Z A1AT from cells. Berthelier et al (PLOS ONE, May 11, 2015) have demonstrated that S-(4-nitrobenzyl)-6-thioguanosine is able to prevent Z A1AT polymerisation in vitro. Mallya et al (J. Med. Chem., 2007, 50, 22, 5357-5363) describe a series of phenols, such as N-(4-hydroxy-3,5-dimethylphenyl)-2,5-dimethylthiophene-3-sulfonamide, able to block polymerisation of Z A1AT in vitro. Huntington (XIIIth International Symposium on Proteinases, Inhibitors and Biological Control, 23 Sep. 2012, and 7th International Symposium on Serpin Biology, Structure and Function, 1 Apr. 2014) discussed a cavity from an X-ray crystal structure of Z A1AT that is a potential target for rational drug design to develop agents that will affect Z A1AT polymerisation. U.S. Pat. No. 8,436,013B2 discloses a wide variety of structures able to increase secretion of Z A1AT from cells in the micromolar range. WO2019/243841A1 describes compounds designed to inhibit Z A1AT polymerisation by inducing formation of a cryptic binding site within the A1AT protein structure. WO2020/081257A1 describes compounds which are able to modulate A1AT activity, as measured using a Z A1AT ela