Trifluoromethyl Dihydrothiazine‐Based β‐Secretase (BACE1) Inhibitors with Robust Central β‐Amyloid Reduction and Minimal Covalent Binding Burden

• Published in: ChemMedChem Vol. 14; no. 22; pp. 1894 - 1910
• Main Authors: 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, Kenichi
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 20-11-2019
• Subjects: Alzheimer's disease; Amyloid precursor protein; BACE1; Binding; covalent binding burden; dihydrothiazine; Dogs; Dosage; Efflux; Hepatocytes; Hepatotoxicity; Medical treatment; Metabolites; Microsomes; Neurodegenerative diseases; Optimization; Oral administration; Prolongation; Pyrazine; reactive metabolite; Reduction; Secretase; β-secretase; β-Site APP-cleaving enzyme 1; BACE1; β-secretase; covalent binding burden; reactive metabolite; hepatotoxicity; dihydrothiazine
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201900478

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 pKa lowering approach over the initial leads was adopted to mitigate hERG inhibition and P‐gp efflux, leading to the design of 6‐CF3 dihydrothiazine 8 (N‐(3‐((4S,6S)‐2‐amino‐4‐methyl‐6‐(trifluoromethyl)‐5,6‐dihydro‐4H‐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‐4H‐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 [14C]‐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.
Minimal covalent binding (CVB) burden: BACE1 inhibitor 15 elicited robust β‐amyloid reduction in dog with an EC50 value of 29 ng/mL. Although the potential for reactive metabolite formation of 15 was realized in a nucleophile trapping assay using [14C]‐KCN in human liver microsomes, the daily CVB burden was calculated to be at an acceptable value of less than 1 mg/day.