Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity

Aldehyde dehydrogenases (ALDHs) are responsible for the metabolism of aldehydes (exogenous and endogenous) and possess vital physiological and toxicological functions in areas such as CNS, inflammation, metabolic disorders, and cancers. Overexpression of certain ALDHs (e.g., ALDH1A1) is an important biomarker in cancers and cancer stem cells (CSCs) indicating the potential need for the identification and development of small molecule ALDH inhibitors. Herein, a newly designed series of quinoline-based analogs of ALDH1A1 inhibitors is described. Extensive medicinal chemistry optimization and biological characterization led to the identification of analogs with significantly improved enzymatic and cellular ALDH inhibition. Selected analogs, e.g., 86 (NCT-505) and 91 (NCT-506), demonstrated target engagement in a cellular thermal shift assay (CETSA), inhibited the formation of 3D spheroid cultures of OV-90 cancer cells, and potentiated the cytotoxicity of paclitaxel in SKOV-3-TR, a paclitaxel resistant ovarian cancer cell line. Lead compounds also exhibit high specificity over other ALDH isozymes and unrelated dehydrogenases. The in vitro ADME profiles and pharmacokinetic evaluation of selected analogs are also highlighted.


Synthesis of compounds 18ab
Compounds 18ab were prepared from compounds 16ab, respectively, according to the similar procedure described in compound 17.

S36
The title compound was prepared from 11d following the similar procedure as described

S38
The title compound was prepared from 11h following the similar procedure as described

48
The title compound was prepared from 17 following the similar procedure as described in

50
The title compound was prepared from 17 following the similar procedure as described in

52
The title compound was prepared from 17 following the similar procedure as described in

dimethylpiperazine-1-carboxamide, TFA (53) 53
The title compound was prepared from 12 following the similar procedure as described in

54
The title compound was prepared from 12 following the similar procedure as described in

56
The title compound was prepared from 12 following the similar procedure as described in

dimethylpiperazine-1-sulfonamide, TFA (57) 57
The title compound was prepared from 12 following the similar procedure as described in

58
The title compound was prepared from 12 following the similar procedure as described in

60
The title compound was prepared from 12 following the similar procedure as described in

62
The title compound was prepared from 12 following the similar procedure as described in

64
The title compound was prepared from 12 following the similar procedure as described in

81
The title compound was prepared from 19 following the similar procedure as described in

89
The title compound was prepared from 18b following the similar procedure as described  + : 470.1908, found: 470.1922.

91
The title compound was prepared from 18b following the similar procedure as described Alternatively, compound 91 can be prepared from 21a following the similar procedure as described in the synthesis of 117. The product was purified by silica gel chromatography using 0-10% MeOH/EtOAc as the eluent to give 1- piperazine-1carbonyl)quinolin-4-yl)phenyl)cyclopropanecarbonitrile.

100
The title compound was prepared from 18a following the similar procedure as described  The title compound was prepared from 18a following the similar procedure as described

107
The title compound was prepared from 13f following the similar procedure as described

108
The title compound was prepared from 13f following the similar procedure as described The title compound was prepared from 21b following the similar procedure as described in the synthesis of 117. The product was purified by silica gel chromatography using 0-10% MeOH/EtOAc as the eluent and then converted to its HCl salt according to t he similar procedure as described in the synthesis of 86. 1  The title compound was prepared from 21f following the similar procedure as described in the synthesis of 117. The product was purified by silica gel chromatography using 0-10%