2. Academic Validation
  3. Lead Optimization Generates CYP11B1 Inhibitors of Pyridylmethyl Isoxazole Type with Improved Pharmacological Profile for the Treatment of Cushing's Disease

Lead Optimization Generates CYP11B1 Inhibitors of Pyridylmethyl Isoxazole Type with Improved Pharmacological Profile for the Treatment of Cushing's Disease

  • J Med Chem. 2017 Jun 22;60(12):5086-5098. doi: 10.1021/acs.jmedchem.7b00437.
Juliette Emmerich 1,  Chris J van Koppen 2,  Jens L Burkhart 2,  Qingzhong Hu 3,  Lorenz Siebenbürger 4,  Carsten Boerger 4,  Claudia Scheuer 5,  Matthias W Laschke 5,  Michael D Menger 5,  Rolf W Hartmann 1 3
Affiliations

Affiliations

  • 1 Pharmaceutical and Medicinal Chemistry, Saarland University , Campus E8.1, 66123 Saarbrücken, Germany.
  • 2 Elexopharm GmbH , Campus A1, 66123 Saarbrücken, Germany.
  • 3 Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus E8.1, 66123 Saarbrücken, Germany.
  • 4 PharmBioTec GmbH , Science Park 1, 66123 Saarbrücken, Germany.
  • 5 Institute for Clinical and Experimental Surgery, Saarland University , 66421 Homburg, Saar, Germany.
PMID: 28570067 DOI: 10.1021/acs.jmedchem.7b00437
Abstract

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.

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