jm9b01034_si_002.csv (3.38 kB)
Discovery of AM-6494: A Potent and Orally Efficacious β‑Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor with in Vivo Selectivity over BACE2
dataset
posted on 2019-10-18, 16:39 authored by Liping H. Pettus, Matthew P. Bourbeau, Jodi Bradley, Michael D. Bartberger, Kui Chen, Dean Hickman, Michael Johnson, Qingyian Liu, James R. Manning, Adrian Nanez, Aaron C. Siegmund, Paul H. Wen, Douglas A. Whittington, Jennifer R. Allen, Stephen Woodβ-Site amyloid
precursor protein cleaving enzyme 1 (BACE1)
is an aspartyl protease that plays a key role in the production of
amyloid β (Aβ) in the brain and has been extensively pursued
as a target for the treatment of Alzheimer’s disease (AD).
BACE2, an aspartyl protease that is structurally related to BACE1,
has been recently reported to be involved in melanosome maturation
and pigmentation. Herein, we describe the development of a series
of cyclopropylthiazines as potent and orally efficacious BACE1 inhibitors.
Lead optimization led to the identification of 20, a
molecule with biochemical IC50 BACE2/BACE1 ratio of 47.
Administration of 20 resulted in no skin/fur color change
in a 13-day mouse hypopigmentation study and demonstrated robust and
sustained reduction of CSF and brain Aβ40 levels
in rat and monkey pharmacodynamic models. On the basis of a compelling
data package, 20 (AM-6494) was advanced to preclinical
development.