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Chymase (EC 3.4.21.39) is a chymotrypsin-like serine protease present in the secretory granules of mast cells, located mainly in the heart, blood vessels, and skin of in many mammalian species. Its physiological substrate is angiotensin I, which upon cleavage by chymase yields angiotensin II in steps of the renin-angiotensin system. In addition it is known to promote mast cell degranulation and plays a role in airway secretions and in atopic or allergic inflammation of the skin. Therefore chymase is regarded as a potential therapeutic target for cardiovascular diseases as well as allergic/inflammatory diseases. SPF-32629A (1) and B (2) were isolated from the cultured broth of Penicillium sp. SPF-32629 and have the inhibitory activities against human chymase with the IC50 of 0.25 and 0.42 μg/mL, respectively, as selective inhibitors. They have a 4-hydroxy-2-pyridone skeleton on phenylmethanol (Figure 1). Mukkanti group reported first synthesis and structural determination of 1 and 2, however there were not the analogs developed for chymase inhibition so far. In this work, 2and 4-pyridone analogs of SPF-32629A were synthesized via short and efficient routes and evaluated as chymase inhibitors in order to establish SAR such as the necessity of 4-hydroxy-2-pyridone and the effects on C4' modification of phenyl group (a) with p-fluorophenyl (b), pchlorophenyl (c), p-tolyl (d) and p-methoxyphenyl (e). Our synthetic route for 2-pyridones is shown in Scheme 1. First, aryl(2-pyridinyl)methanols (3a-e) were synthesized by Grignard reagents addition to the starting material 6-methoxy-2-pyridinecarboxaldehyde. The treatment of 3 with TMSI afforded the 2-pyridones (4a-e), which were converted into the isovalerates (5a-e) along with bis-isovalerates (6a-e) under EDCI-mediated condition. The isovalerate (7a3) was also prepared from 4 in a similar manner. 4-Pyridone analogs of SPF-32629A were synthesized from the known nitrile (8) (Scheme 2). The ketones (9a-e) were given by Grignard reagents addition to 8, followed by acid treatment. With 9 in hands, NaBH4 reduction and subsequent hydrogenolysis of the alcohol (10a-e) afforded the 4-pyridones (11a-e). Finally, 11 were converted into the isovalerates (12a-e). The diesters (13a-e) were easily hydrolyzed to afford the corresponding 12. The inhibitory effect on chymase of SPF-32629A analogs at 100 μM is shown in Figure 2. The IC50 of selected analogs was tested as shown as Table 1. The introduction of 2methoxypyridine (3 and 7) and 4-benzyloxypyridine (9 and 10) instead of 2and 4-pyridone resulted in a loss of activity.

Synthesis, Biological Evaluation of SPF-32629A-Based 2- and 4-Pyridone Analogs as Chymase Inhibitors