1. Discovery of Novel and Potent Stearoyl Coenzyme A Desaturase 1 (SCD1) Inhibitors as Anticancer Agents.
- Author
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Imamura K, Tomita N, Kawakita Y, Ito Y, Ono K, Nii N, Miyazaki T, Yonemori K, Tawada M, Sumi H, Satoh Y, Yamamoto Y, Miyahisa I, Sasaki M, Satomi Y, Hirayama M, Nishigaki R, and Maezaki H
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Colonic Neoplasms drug therapy, Drug Evaluation, Preclinical, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, HCT116 Cells, Humans, Inhibitory Concentration 50, Mice, Mice, Inbred BALB C, Mice, Nude, Microsomes, Liver metabolism, Oxadiazoles pharmacokinetics, Oxadiazoles therapeutic use, Oxadiazoles toxicity, Piperidines chemistry, Piperidines metabolism, Piperidines pharmacology, Protein Binding, Pyridazines pharmacokinetics, Pyridazines therapeutic use, Pyridazines toxicity, Spiro Compounds chemistry, Stearoyl-CoA Desaturase metabolism, Structure-Activity Relationship, Transplantation, Heterologous, Antineoplastic Agents chemistry, Enzyme Inhibitors chemical synthesis, Oxadiazoles chemical synthesis, Pyridazines chemical synthesis, Stearoyl-CoA Desaturase antagonists & inhibitors
- Abstract
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 0.3mg/kg, bid) in HCT116 mouse xenograft model and tumor growth suppression (at 1mg/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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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