- Lead Optimization Generates CYP11B1 Inhibitors of Pyridylmethyl Isoxazole Type with Improved Pharmacological Profile for the Treatment of Cushing's Disease
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Cushing's disease, characterized by elevated plasma cortisol levels, can be controlled by inhibition of 11β-hydroxylase (CYP11B1). The previously identified selective and potent CYP11B1 inhibitor 5-((5-methylpyridin-3-yl)methyl)-2-phenylpyridine Ref 7 (IC50= 2 nM) exhibited promutagenic potential as well as very low oral bioavailability in rats (F = 2%) and was therefore modified to overcome these drawbacks. Successful lead optimization resulted in similarly potent and selective 5-((5-methoxypyridin-3-yl)methyl)-3-phenylisoxazole 25 (IC50 = 2 nM, 14-fold selectivity over CYP11B2), exhibiting a superior pharmacological profile with no mutagenic potential. Furthermore, compound 25 inhibited rat CYP11B1 (IC50 = 2 μM) and showed a high oral bioavailability (F = 50%) and sufficient plasma concentrations in rats, providing an excellent starting point for a proof-of-principle study.
- Emmerich, Juliette,Van Koppen, Chris J.,Burkhart, Jens L.,Hu, Qingzhong,Siebenbürger, Lorenz,Boerger, Carsten,Scheuer, Claudia,Laschke, Matthias W.,Menger, Michael D.,Hartmann, Rolf W.
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supporting information
p. 5086 - 5098
(2017/06/28)
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- Inhibitors of viral replication, their process of preparation and their therapeutical uses
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The present invention relates to compounds of formula (I), their use in the treatment or the prevention of viral disorders, including HIV. wherein R1, R2, R3 and R4 are as included in the claims.
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Page/Page column
(2014/05/06)
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