2. Academic Validation
  3. Trifluoromethyl Dihydrothiazine-Based β-Secretase (BACE1) Inhibitors with Robust Central β-Amyloid Reduction and Minimal Covalent Binding Burden

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

  • ChemMedChem. 2019 Nov 20;14(22):1894-1910. doi: 10.1002/cmdc.201900478.
Kosuke Anan 1,  Yasuyoshi Iso 1,  Takuya Oguma 1,  Kenji Nakahara 1,  Shinji Suzuki 1,  Takahiko Yamamoto 1 2,  Eriko Matsuoka 1,  Hisanori Ito 1,  Gaku Sakaguchi 1,  Shigeru Ando 3,  Kenji Morimoto 3,  Naoki Kanegawa 3,  Yasuto Kido 3,  Tomoyuki Kawachi 3,  Tamio Fukushima 3,  Ard Teisman 4,  Vijay Urmaliya 4,  Deborah Dhuyvetter 4,  Herman Borghys 4,  Nigel Austin 5 6,  An Van Den Bergh 5,  Peter Verboven 5,  Francois Bischoff 5,  Harrie J M Gijsen 5,  Yoshinori Yamano 1,  Kenichi Kusakabe 1
Affiliations

Affiliations

  • 1 Discovery Research Laboratory for Core Therapeutic Areas, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka, 561-0825, Japan.
  • 2 Current address: API Process Development Department (Biotechnology), Pharmaceutical Technology Division, Chugai Pharmaceutical Co., Ltd., 5-1, Ukima 5-chome, Kita-ku, Tokyo, 115-8543, Japan.
  • 3 Research Laboratory for Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka, 561-0825, Japan.
  • 4 Non-Clinical Safety, Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
  • 5 Discovery Sciences, Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
  • 6 Current address: Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge, CB21 6DG, UK.
PMID: 31657130 DOI: 10.1002/cmdc.201900478
Abstract

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 [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.

Keywords

BACE1; covalent binding burden; dihydrothiazine; hepatotoxicity; reactive metabolite; β-secretase.

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