Modulation of Pharmacologically Relevant Properties of Piperidine Derivatives by Functional Groups in an Equatorial or Axial ß-Position to the Amino Group.

Thirteen epimeric pairs of 5-substituted N-piperonyl-3-phenylpiperidine derivatives were synthesized in order to explore the stereospecific modulation of basicity, lipophilicity, aqueous solubility, and membrane permeation by functional groups in equatorial or axial positions beta to the amine unit. While this comprehensive data set provides enhanced insight into multiple factors that affect basicity and lipophilicity, it fills an important knowledge gap, providing a frame of reference for the property-based design of bioactive compounds. Impacts on amine basicity are very pronounced for the ß-equatorial functional groups and parallel basicity-lowering effects known for acyclic amine derivatives. For ß-axial functional groups, the basicity-lowering effects are generally decreased, with the nitrile group as the only exception. Basicity and lipophilicity modulations observed for ß-axial functional groups are quite diverse and rationalized in terms of intramolecular hydrogen bonding, dipolar interactions, and special solvation effects. Aqueous solubility and (artificial) membrane permeability are discussed with reference to lipophilicity.

An intramolecular [2 + 2] photocycloaddition approach to conformationally restricted bis-pyrrolidines.

With N-Boc-protected 4-(allylaminomethyl)-2(5H)furanones as starting materials, a photochemical approach is presented to give 3,9-diazatricyclo[5.3.0.0(1,5)]decanes as conformationally restricted bis-pyrrolidines. The products are orthogonally protected at the two nitrogen atoms and exhibit, depending on the substitution pattern at positions C5, C6, and C7, latent C2 symmetry. When the furanones had a phenyl group at the 3-position (X(3)), alternative photochemical pathways were observed.

CELLOPT: improved unit-cell parameters for electron diffraction data of small-molecule crystals.

Electron diffraction enables structure determination of organic small molecules using crystals that are too small for conventional X-ray crystallography. However, because of uncertainties in the experimental parameters, notably the detector distance, the unit-cell parameters and the geometry of the structural models are typically less accurate and precise compared with results obtained by X-ray diffraction. Here, an iterative procedure to optimize the unit-cell parameters obtained from electron diffraction using idealized restraints is proposed. The cell optimization routine has been implemented as part of the structure refinement, and a gradual improvement in lattice parameters and data quality is demonstrated. It is shown that cell optimization, optionally combined with geometrical corrections for any apparent detector distortions, benefits refinement of electron diffraction data in small-molecule crystallography and leads to more accurate structural models.

Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439.

OZ439 is a potent synthetic ozonide evaluated for the treatment of uncomplicated malaria. The metabolite profile of OZ439 was characterized in vitro using human liver microsomes combined with LC/MS-MS, chemical derivatization, and metabolite synthesis. The primary biotransformations were monohydroxylation at the three distal carbon atoms of the spiroadamantane substructure, with minor contributions from N-oxidation of the morpholine nitrogen and deethylation cleavage of the morpholine ring. Secondary transformations resulted in the formation of dihydroxylation metabolites and metabolites containing both monohydroxylation and morpholine N-oxidation. With the exception of two minor metabolites, none of the other metabolites had appreciable antimalarial activity. Reaction phenotyping indicated that CYP3A4 is the enzyme responsible for the metabolism of OZ439, and it was found to inhibit CYP3A via both direct and mechanism-based inhibition. Elucidation of the metabolic pathways and kinetics will assist with efforts to predict potential metabolic drug-drug interactions and support physiologically based pharmacokinetic (PBPK) modeling.

Substituted 2-oxo-azepane derivatives are potent, orally active gamma-secretase inhibitors.

A hydroxamic acid screening hit 1 was elaborated to 5,5-dimethyl-2-oxoazepane derivatives exhibiting low nanomolar inhibition of gamma-secretase, a key proteolytic enzyme involved in Alzheimer's disease. Early ADME data showed a high metabolic clearance for the geminal dimethyl analogs which could be overcome by replacement with the bioisosteric geminal difluoro group. Synthesis and structure-activity relationship are discussed and in vivo active compounds are presented.

Is adamantane a suitable substituent to pre-organize the acid orientation in E-selectin antagonists?

The selectins play a key role in the inflammatory process, that is, the recruitment of leukocytes from blood vessels into inflamed tissue. Because excessive infiltration of leukocytes can induce acute or chronic reactions, the control of leukocyte extravasation is of great pharmaceutical interest. All physiological ligands of the selectins contain the tetrasaccharide epitope sialyl Lewis(x), which therefore became the lead structure in selectin antagonist research. Previous studies indicated that an important factor for the affinity of sLe(x) is the fact that in solution its pharmacophores are already conformationally pre-organized in the bioactive orientation. In mimics where the GlcNAc- and the NeuNAc-moieties of sLe(x) were replaced by (R,R)-cyclohexane-1,2-diol and (S)-cyclohexyllactic acid, respectively, an optimized pre-organization of the pharmacophores could be realized, leading to antagonists with improved affinities. To further optimize the pre-organization of the carboxylic acid, a pharmacophore essential for binding, the replacement of NeuNAc by bulky (R)- and (S)-adamantyl-lactic acid was studied. Although antagonist (S)-7 showed a slightly reduced affinity, the expected beneficial effect of the (S)-configuration at C-2 of the lactate could be confirmed.

Discovery of 4-Aryl-5,6,7,8-tetrahydroisoquinolines as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors: In Vivo Evaluation in Rodents and Cynomolgus Monkeys.

Inappropriately high levels of aldosterone are associated with many serious medical conditions, including renal and cardiac failure. A focused screen hit has been optimized into a potent and selective aldosterone synthase (CYP11B2) inhibitor with in vitro activity against rat, mouse, human, and cynomolgus monkey enzymes, showing a selectivity factor of 160 against cytochrome CYP11B1 in the last species. The novel tetrahydroisoquinoline compound (+)-(R)-6 selectively reduced aldosterone plasma levels in vivo in a dose-dependent manner in db/db mice and cynomolgus monkeys. The selectivity against CYP11B1 as predicted by cellular inhibition data and free plasma fraction translated well to Synacthen challenged cynomolgus monkeys up to a dose of 0.1 mg kg(-1). This compound, displaying good in vivo potency and selectivity in mice and monkeys, is ideally suited to perform mechanistic studies in relevant rodent models and to provide the information necessary for translation to non-human primates and ultimately to man.