Novel Aldosterone Synthase Inhibitors with Extended Carbocyclic Skeleton by a Combined Ligand-Based and Structure-Based Drug Design Approach

• DOI: 10.1021/jm800683c
• Publication Date: 2008-09-03T08:00:29Z
• Authors: Simon Lucas; Ralf Heim; Matthias Negri; Iris Antes; Christina Ries; Katarzyna E. Schewe; Alessandra Bisi; Silvia Gobbi; Rolf W. Hartmann
• Keywords: Models, Molecular; 0303 health sciences; Binding Sites; Dose-Response Relationship, Drug; Molecular Structure; Acids, Carbocyclic; Stereoisomerism; Naphthalenes; Crystallography, X-Ray; Ligands; Structure-Activity Relationship; 03 medical and health sciences; Models, Chemical; Drug Design; Cytochrome P-450 CYP11B2; Humans; Computer Simulation

Pharmacophore modeling of a series of aldosterone synthase (CYP11B2) inhibitors triggered the design of compounds 11 and 12 by extending a previously established naphthalene molecular scaffold (e.g., present in molecules 1 and 2) via introduction of a phenyl or benzyl residue in 3-position. These additional aromatic moieties have been hypothesized to fit into the newly identified hydrophobic pharmacophore feature HY3. Subsequent docking studies in our refined CYP11B2 protein model have been performed prior to synthesis to estimate the inhibitory properties of the proposed molecules. While phenyl-substituted compound 11 (IC50 > 500 nM) did not dock under the given pharmacophore constraint (i.e., the Fe(heme)-N(ligand) interaction), benzyl-substituted compound 12 (IC50 = 154 nM) was found to exploit a previously unexplored subpocket of the inhibitor binding site. By structural optimization based on the pharmacophore hypothesis, 25 novel compounds were synthesized, among them highly potent CYP11B2 inhibitors (e.g., 17, IC50 = 2.7 nM) with pronounced selectivity toward the most important steroidogenic and hepatic CYP enzymes.