Discovery of Novel and Potent Stearoyl Coenzyme A Desaturase 1 (SCD1) Inhibitors as Anticancer Agents

Publication date: Available online 11 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Keisuke Imamura, Naoki Tomita, Youichi Kawakita, Yoshiteru Ito, Kouji Ono, Noriyuki Nii, Tohru Miyazaki, Kazuko Yonemori, Michiko Tawada, Hiroyuki Sumi, Yoshihiko Satoh, Yukiko Yamamoto, Ikuo Miyahisa, Masako Sasaki, Yoshinori Satomi, Megumi Hirayama, Ryuichi Nishigaki, Hironobu Maezaki
A lead compound A was identified previously as an stearoyl coenzyme A desaturase (SCD) inhibitor during research on potential treatments for obesity. This compound showed high SCD1 binding affinity, but a poor pharmacokinetic (PK) profile and limited chemical accessibility, making it suboptimal for use in anticancer research. To identify potent SCD1 inhibitors with more promising PK profiles, we newly designed a series of 'non-spiro' 4, 4-disubstituted piperidine derivatives based on molecular modeling studies. As a result, we discovered compound 1a, which retained moderate SCD1 binding affinity. Optimization around 1a was accelerated by analyzing Hansch–Fujita and Hammett constants to obtain 4-phenyl-4-(trifluoromethyl)piperidine derivative 1n. Fine-tuning of the azole moiety of 1n led to compound 1o (T-3764518), which retained nanomolar affinity and exhibited an excellent PK profile. Reflecting the good potency and PK profile, orally administrated compound 1o showed significant pharmacodynamic (PD) marker reduction (at 0.3 mg/kg, bid) in HCT116 mouse xenograft model and tumor growth suppression (at 1 mg/kg, bid) in 786-O mouse xenograft model.In conclusion, we identified a new series of SCD1 inhibitors, represented by compound 1o, which represents a promising new chemical tool suitable for the study of SCD1 biology as well as the potential development of novel anticancer therapies.

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