1309364-59-7

Upstream product

• 73568-35-1 6-bromo-2-chloro-3-formylquinoline 
• 103-88-8 4-bromoacetanilide 
• 1309366-05-9 3-(2-(tert-butylamino)-6-o-tolylquinolin-3-yl)-2-methylpropanoic acid 
• 1309366-04-8 ethyl 3‐[2‐(tert‐butylamino)‐6‐(2‐methylphenyl)quinolin‐3‐yl]‐2‐methylpropanoate 
• 1321992-43-1 ethyl 3-(2-(tert-butylamino)-6-o-tolylquinolin-3-yl)-2-methylacrylate 
• 1308870-06-5 2-(tert-butylamino)-6-bromoquinoline-3-carbaldehyde 

Relevant academic research and scientific papers

From fragment screening to in vivo efficacy: Optimization of a series of 2-aminoquinolines as potent inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (bace1)

Using fragment-based screening of a focused fragment library, 2-aminoquinoline 1 was identified as an initial hit for BACE1. Further SAR development was supported by X-ray structures of BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery of potent compounds. These strategies enabled us to integrate the C-3 side chain on 2-aminoquinoline 1 extending deep into the P2′ binding pocket of BACE1 and enhancing the ligand's potency. We were able to improve the BACE1 potency to subnanomolar range, over 106-fold more potent than the initial hit (900 μM). Further elaboration of the physical properties of the lead compounds to those more consistent with good blood-brain barrier permeability led to inhibitors with greatly improved cellular activity and permeability. Compound 59 showed an IC50 value of 11 nM on BACE1 and cellular activity of 80 nM. This compound was advanced into rat pharmacokinetic and pharmacodynamic studies and demonstrated significant reduction of Aβ levels in cerebrospinal fluid (CSF).

AMINO HETEROARYL COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE

The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer?s disease (AD) and related conditions. In one embodiment, the compounds have a general Formula I wherein ring A, B1, B2, B3, L, R1, R4, R5 and m of Formula I are defined herein. The invention also includes use of these compounds in pharmaceutical compositions for treatment, prophylactic or therapeutic, of disorders and conditions related to the activity of beta-secretase protein. Such disorders include, for example, Alzheimer?s Disease (AD), cognitive deficits, cognitive impairment, schizophrenia and other central nervous system conditions related to and/or caused by the formation and/or deposition of plaque on the brain. The invention also comprises further embodiments of Formula I, intermediates and processes useful for the preparation of compounds of Formula I