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
  • 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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