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. 2021 Dec 1;13(1):76-83.
doi: 10.1021/acsmedchemlett.1c00445. eCollection 2022 Jan 13.

A Brain-Penetrant and Bioavailable Pyrazolopiperazine BACE1 Inhibitor Elicits Sustained Reduction of Amyloid β In Vivo

Aldo Peschiulli  1 , Daniel Oehlrich  1 , Michiel Van Gool  2 , Nigel Austin  1 , Sven Van Brandt  1 , Michel Surkyn  1 , Michel De Cleyn  1 , Ann Vos  1 , Gary Tresadern  1 , Frederik J R Rombouts  1 , Gregor J Macdonald  1 , Diederik Moechars  1 , Andrés A Trabanco  2 , Harrie J M Gijsen  1
Affiliations

A Brain-Penetrant and Bioavailable Pyrazolopiperazine BACE1 Inhibitor Elicits Sustained Reduction of Amyloid β In Vivo

Aldo Peschiulli et al. ACS Med Chem Lett. .

Abstract

We recently disclosed a set of heteroaryl-fused piperazine inhibitors of BACE1 that combined nanomolar potency with good intrinsic permeability and low Pgp-mediated efflux. Herein we describe further work on two prototypes of this family of inhibitors aimed at modulating their basicity and reducing binding to the human ether-a-go-go-related gene (hERG) channel. This effort has led to the identification of compound 36, a highly potent (hAβ42 cell IC50 = 1.3 nM), cardiovascularly safe, and orally bioavailable compound that elicited sustained Aβ42 reduction in mouse and dog animal models.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
BACE1 inhibitors in advanced clinical trials.
Figure 2
Figure 2
Reported heteroaryl-fused piperazine warheads.
Figure 3
Figure 3
Nitrile-substituted imidazopiperazines 8 and 9.
Scheme 1
Scheme 1. Synthesis of Imidazopiperazine BACE1 Inhibitor 8
Reagents and conditions: (a) (Boc)2O, DIPEA, DCM, rt, 48 h (85% yield); (b) n-BuLi (2.7 M in heptane), THF, I2, −78 °C, 1 h (59% yield); (c) Zn(CN)2, Zn, Pd2(dba)3, dppf, DMA, 150 °C, 40 min (45% yield); (d) TFA, DCM, rt, 2 h (68% yield); (e) (Boc)2O, DCM, rt, 5 h (83% yield); (f) 5-cyanopyridine-2-carboxylic acid, DMTMM, MeOH, 0 °C to rt, 16 h (82% yield); (g) TFA, DCM, rt, 2 h (82% yield).
Scheme 2
Scheme 2. Synthesis of Imidazopiperazine BACE1 Inhibitor 9
Reagents and conditions: (a) K2CO3, DMF, 90 °C, 20 h; (b) HCl (4 N in 1,4-dioxane), 60 °C, 2 h (40% yield over two steps); (c) KOH, EtOH, 85 °C, 24 h (95% yield); (d) (Boc)2O, DIPEA, DCM, rt, 1 h (34% yield); (e) Zn(CN)2, Zn, DMA, Pd2(dba)3, dppf, 150 °C, 30 min; (f) TFA, DCM, rt, 30 min (67% yield over two steps); (g) 5-cyanopyridine-2-carboxylic acid, EDCI, HCl (6 N in iPrOH), MeOH, rt, 1 h (87% yield).
Figure 4
Figure 4
Dog in vivo plasma levels of compound 8 and consequent CSF Aβ42 reduction (mean + SEM). Male (n = 2 per dose group) and female (n = 2 per dose group) beagle dogs, fasted.
Scheme 3
Scheme 3. Synthesis of BACE1 Inhibitor Pyrazolopiperazine 30
Reagents and conditions: (a) K2CO3, MeCN, 80 °C, 7 h; (b) formic acid, DCM, 40 °C, 20 h (71% yield over two steps); (c) H2 (1 atm), 10% Pd/C, MeOH, TEA, rt, 4 h (100% yield); (d) HNO3, H2SO4, TFA, −10 °C, 30 min (63% yield); (e) H2 (1 atm), Pt/C, MeOH, 50 °C, 4 h (99% yield); (f) 5-cyanopyridine-2-carboxylic acid, EDCI, HCl (6 N in iPrOH), MeOH, rt, 1 h (64% yield).
Figure 5
Figure 5
Dog in vivo plasma levels of compound 36 and consequent CSF Aβ42 reduction (mean + SEM). Male (n = 2 per dose group) and female (n = 2 per dose group) beagle dogs, fasted.
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