Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase

Abstract

Human acidic mammalian chitinase (hAMCase) is one of two true chitinases in humans, the function of which remains elusive. In addition to the defense against highly antigenic chitin and chitin-containing pathogens in the gastric and intestinal contents, AMCase has been implicated in asthma, allergic inflammation, and ocular pathologies. Potent and selective small-molecule inhibitors of this enzyme have not been identified to date. Here we describe structural modifications of compound OAT-177, a previously developed inhibitor of mouse AMCase, leading to OAT-1441, which displays high activity and selectivity toward hAMCase. Significantly reduced off-target activity toward the human ether-à-go-go-related gene (hERG) and a good pharmacokinetic profile make OAT-1441 a potential candidate for further preclinical development as well as a useful tool compound to study the physiological role of hAMCase.

Figure 1

Selectivities of small-molecule inhibitors toward mouse and human AMCase reported in the literature.

Scheme 1. Synthetic Pathway for Analogues 1, 3, and 6–10

Reagents and conditions: (a) NaBH(OAc)₃, DCE, rt, 99% yield; (b) RCHO, NaBH(OAc)₃, DCE, rt; (c) HCl, EtOAc, rt; (d) S,S′-dimethyl N-cyanodithioiminocarbonate, K₂CO₃, MeCN, reflux; (e) N₂H₄·H₂O, MeCN, reflux, overall 15–32% yield over steps b–e.

Scheme 2. Synthetic Pathway for Analogues 14, 16, and 18

Reagents and conditions: (a) NaBH(OAc)₃, DCE, rt; (b) TBAF, THF or AcOH/H₂O/THF, 65 °C (c) t-BuOK, THF, reflux; (d) N-Boc-piperid-4-one, AcOH, NaBH(OAc)₃, DCE, 75 °C to rt; (e) TFA, DCM, rt; (f) S,S′-dimethyl N-cyanodithioiminocarbonate, K₂CO₃, MeCN, reflux; (g) N₂H₄·H₂O, MeCN, reflux, overall 8–27% yield over steps a–g.

Figure 2

(A, B) Structures of hCHIT1 (A) cocrystallized with 3 (PDB ID 5NRF) and (B) docked with OAT-1441. (C, D) Structures of hAMCase with docked (C) 3 and (D) OAT-1441. Both protein structures are shown in the same orientation.