ABSTRACT
Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aß(42) in various animal models.
Subject(s)
Amidines/chemical synthesis , Amyloid Precursor Protein Secretases/metabolism , Oxadiazoles/chemical synthesis , Oxazines/chemical synthesis , Amidines/pharmacokinetics , Amidines/pharmacology , Amyloid beta-Peptides/metabolism , Animals , Brain/metabolism , Dogs , HEK293 Cells , Humans , Macaca fascicularis , Male , Oxadiazoles/pharmacokinetics , Oxadiazoles/pharmacology , Oxazines/pharmacokinetics , Oxazines/pharmacology , Peptide Fragments/metabolism , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The synthesis of a novel series of iminoheterocycles and their structure-activity relationship (SAR) as modulators of gamma-secretase activity will be detailed. Encouraging SAR generated from a monocyclic core led to a structurally unique bicyclic core. Selected compounds exhibit good potency as gamma-secretase modulators, excellent rat pharmacokinetics, and lowering of Abeta42 levels in various in vivo models.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Imines/chemistry , Imines/therapeutic use , Peptide Fragments/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Animals , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Humans , Imines/pharmacokinetics , Mice , Mice, Transgenic , Peptide Fragments/antagonists & inhibitors , Rats , Structure-Activity RelationshipABSTRACT
The supramolecular assistance to Pd(0)/Cu(I)-catalyzed cyclotrimerization of stannylated norbornene 7 has been investigated to give molecular bowl 1syn in a stereoselective fashion. Following a divergent strategy, racemic norbornene 7 was synthesized in satisfactory yield. Self-coupling, promoted by Pd(0)/Cu(I) catalysis acting in synergy with CsF, yielded molecular bowl 1syn in a moderate 30% yield. The reaction diastereoselectivity is affected by the concentration of Cu(I) and Cs+: increasing quantities of the cations enhanced the syn/anti ratio of the isolated cyclotrimer from statistical (1:3) to a more desirable (4.5:1) ratio, in favor of the molecular bowl 1syn. 1H NMR spectroscopic studies suggested the coordinating affinity of 1syn toward transition metals Cu(I), Ag(I), and Au(I), to account for the observed templation effect. In particular, the tridentate 1syn has been shown to bind to one Ag(I) cation in the assembly process that is driven with enthalpy (Delta H degrees = -19 +/- 2 kcal/mol, Delta S degrees = -45 eu). The complete coordination was not cooperative, and was hypothesized to be impeded with the adverse entropy. Accordingly, density functional theory (BP86) calculations of 1syn and its mono-, bis-, and tris-Ag(I) complexes suggested that the coordination of one to three silver cations is highly exothermic. The calculations also revealed that the bowl constriction is necessary for the aromatic arms to become preorganized and bind to a silver cation(s) (Delta E approximately 8 kcal/mol). Ultimately, Ag(I) has been shown to assist the diastereoselective formation of 1syn, lending support to the notion of template-directed synthesis.
