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Trifluoromethyl Dihydrothiazine‐Based β‐Secretase (BACE1) Inhibitors with Robust Central β‐Amyloid Reduction and Minimal Covalent Binding Burden
Author(s) -
Anan Kosuke,
Iso Yasuyoshi,
Oguma Takuya,
Nakahara Kenji,
Suzuki Shinji,
Yamamoto Takahiko,
Matsuoka Eriko,
Ito Hisanori,
Sakaguchi Gaku,
Ando Shigeru,
Morimoto Kenji,
Kanegawa Naoki,
Kido Yasuto,
Kawachi Tomoyuki,
Fukushima Tamio,
Teisman Ard,
Urmaliya Vijay,
Dhuyvetter Deborah,
Borghys Herman,
Austin Nigel,
Van Den Bergh An,
Verboven Peter,
Bischoff Francois,
Gijsen Harrie J. M.,
Yamano Yoshinori,
Kusakabe Ken-ichi
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900478
Subject(s) - herg , chemistry , trifluoromethyl , pharmacology , microsome , efflux , amyloid precursor protein , ic50 , enzyme , metabolite , stereochemistry , biochemistry , in vitro , medicine , alzheimer's disease , potassium channel , alkyl , disease , organic chemistry
The β‐site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as β‐secretase) is a promising target for the treatment of Alzheimer's disease. A p K a lowering approach over the initial leads was adopted to mitigate hERG inhibition and P‐gp efflux, leading to the design of 6‐CF 3 dihydrothiazine 8 ( N ‐(3‐((4S,6S)‐2‐amino‐4‐methyl‐6‐(trifluoromethyl)‐5,6‐dihydro‐4 H ‐1,3‐thiazin‐4‐yl)‐4‐fluorophenyl)‐5‐cyanopicolinamide). Optimization of 8 led to the discovery of 15 ( N ‐(3‐((4S,6S)‐2‐amino‐4‐methyl‐6‐(trifluoromethyl)‐5,6‐dihydro‐4 H ‐1,3‐thiazin‐4‐yl)‐4‐fluorophenyl)‐5‐(fluoromethoxy)pyrazine‐2‐carboxamide) with an excellent balance of potency, hERG inhibition, P‐gp efflux, and metabolic stability. Oral administration of 8 elicited robust Aβ reduction in dog even at 0.16 mg/kg. Reflecting the reduced hERG inhibitory activity, no QTc prolongation was observed at high doses. The potential for reactive metabolite formation of 15 was realized in a nucleophile trapping assay using [ 14 C]‐KCN in human liver microsomes. Utilizing covalent binding (CVB) in human hepatocytes and the maximum projected human dosage, the daily CVB burden of 15 was calculated to be at an acceptable value of below 1 mg/day. However, hepatotoxicity was observed when 15 was subjected to a two‐week tolerance study in dog, which prevented further evaluation of this compound.