No abstract

A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (Aβ), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Aβ is produced by the sequential cleavage of APP by BACE1 and γ-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Aβ in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Aβ lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Aβ in rodents and in monkey.

This study was conducted to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of two novel inhibitors of b-site amyloid precursor protein (APP)-cleaving enzyme (BACE1), 4a9S,10a9S)-2-amino-89-(2-fluoropyridin-3-yl)- 1-methyl-39,49,4a9,10a9-tetrahydro-19H-spiro[imidazole-4,109-pyrano[4,3-b] , and to develop a PK-PD model to predict in vivo effects based solely on in vitro activity and PK. GNE-629 and GNE-892 concentrations and PD biomarkers including amyloid b (Ab) in the plasma and cerebrospinal fluid (CSF), and secreted APPb (sAPPb) and secreted APPa (sAPPa) in the CSF were measured after a single oral administration of GNE-629 (100 mg/kg) or GNE-892 (30 or 100 mg/kg) in cynomolgus monkeys. A mechanistic PK-PD model was developed to simultaneously characterize the plasma Ab and CSF Ab, sAPPa, and sAPPb using GNE-629 in vivo data. This model was used to predict the in vivo effects of GNE-892 after adjustments based on differences in in vitro cellular activity and PK. The PK-PD model estimated GNE-629 CSF and free plasma IC 50 of 0.0033 mM and 0.065 mM, respectively. These differences in CSF and free plasma IC 50 suggest that different mechanisms are involved in Ab formation in these two compartments. The predicted in vivo effects for GNE-892 using the PK-PD model were consistent with the observed data. In conclusion, a PK-PD model was developed to mechanistically describe the effects of BACE1 inhibition on Ab, sAPPb, and sAPPa in the CSF, and Ab in the plasma. This model can be used to prospectively predict in vivo effects of new BACE1 inhibitors using just their in vitro activity and PK data.

An efficient method for the selective "N1" alkylation of indazoles is described. Use of alpha-halo esters, lactones, ketones, amides, and bromoacetonitrile provides good to excellent yield of the desired N1 products.

In an attempt to increase selectivity vs Cathepsin D (CatD) in our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyrano[4,3-b]chromene analogues was developed. Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Using structure-based design, substitutions to improve binding to both the S3 and S2' sites of BACE1 were explored. An acyl guanidine moiety provided the most potent analogues. These compounds demonstrated 10-420 fold selectivity for BACE1 vs CatD, and were highly potent in a cell assay measuring Aβ1-40 production (5-99 nM). They also suffered from high efflux. Despite this undesirable property, two of the acyl guanidines achieved free brain concentrations (Cfree,brain) in a guinea pig PD model sufficient to cover their cell IC50s. Moreover, a significant reduction of Aβ1-40 in guinea pig, rat, and cyno CSF (58%, 53%, and 63%, respectively) was observed for compound 62.

Zwei Wege, ein Ziel: Zwei unterschiedliche Synthesestrategien wurden ausgearbeitet, mit denen die Knüpfung der sterisch überfrachteten C8‐C14‐Bindung des präparativ herausfordernden Syntheseziels Azadirachtin 1 gelingen könnte: Beim ersten Ansatz wurde eine Radikalreaktion genutzt, die zur Modellverbindung 2 führte, der zweite beruht auf einer Nickel‐vermittelten Kupplung und lieferte die Modellverbindung 3.

A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37-137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Aβ1-40 at 60 mg/kg (PO).

2002 ring closure reactions ring closure reactions O 0130 31 -035 Iodine(V) Reagents in Organic Synthesis. Part 3. New Routes to Heterocyclic Compounds via o-Iodoxybenzoic Acid-Mediated Cyclizations: Generality, Scope, and Mechanism. -o-Iodoxybenzoic acid (IBX) is used for the synthesis of a wide variety (ca. 100 examples) of δ-lactams, cyclic urethanes, hydroxy amines, and amino sugars, among them important building blocks and intermediates, from certain unsaturated N-aryl amides. -(NICOLAOU, K. C.; BARAN, P. S.; ZHONG, Y.-L.; BARLUENGA, S.; HUNT, K. W.; KRANICH, R.; VEGA, J. A.; J.