Discovery of Novel and Potent Stearoyl Coenzyme A Desaturase 1 (SCD1) Inhibitors as Anticancer Agents. Issue 14 (15th July 2017)

• Record Type: Journal Article
• Authors: Imamura, Keisuke; Tomita, Naoki; Kawakita, Youichi; Ito, Yoshiteru; Ono, Kouji; Nii, Noriyuki; Miyazaki, Tohru; Yonemori, Kazuko; Tawada, Michiko; Sumi, Hiroyuki; Satoh, Yoshihiko; Yamamoto, Yukiko; Miyahisa, Ikuo; Sasaki, Masako; Satomi, Yoshinori; Hirayama, Megumi; Nishigaki, Ryuichi; Maezaki, Hironobu
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 14(2017)
• Page Start: 3768
• Page End: 3779
• Publication Date: 2017-07-15
• Subjects: Ac acetyl -- ADME absorption, distribution, metabolism, and excretion -- aq. aqueous -- AUC total area under the blood concentration–time curve -- bid bis in die (twice per day) -- Boc (tert-butoxy)carbonyl -- Bu butyl -- Bz benzoyl -- cLogP calculate logarithm of the octanolwater partition coefficient -- Cltotal total body clearance -- CPME cyclopentyl methyl ether -- DI desaturation index -- DIPEA N, N-diisopropylethylamine -- DMA N, N-dimethylacetamide -- DMF N, N-dimethylformamide -- DMSO dimethyl sulfoxide -- Et ethyl -- ER endoplasmic reticulum -- Fu unbound fraction -- GI growth inhibition -- HBA hydrogen bond acceptor -- HBD hydrogen bond donor -- IPA 2-propanol -- IPE diisopropyl ether -- LMS liver microsomal stability -- m meta -- Me methyl -- MRT mean residence time -- MW molecular weight -- o ortho -- p para -- PC phosphatidylcholine -- PD pharmacodynamic -- Pd/C palladium on carbon -- PK pharmacokinetic -- PMB p-methoxybenzyl -- Pr propyl -- po per os (oral administration) -- quant. quantitative yield -- rt room temperature -- SAR structureactivity relationship -- sat. saturated aqueous -- SCD stearoyl coenzyme A desaturase -- TEA triethylamine -- tert tertiary -- TFA trifluoroacetic acid -- THF tetrahydrofuran -- Ts tosyl; Stearoyl coenzyme A desaturase 1 -- SCD1 -- 4, 4-Disubstituted piperidine -- Cancer -- Antitumor efficacy -- T-3764518; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.05.016
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A lead compoundA 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 compound1a, which retained moderate SCD1 binding affinity. Optimization around1a was accelerated by analyzing Hansch–Fujita and Hammett constants to obtain 4-phenyl-4-(trifluoromethyl)piperidine derivative1n . Fine-tuning of the azole moiety of1n led to compound1o (T-3764518 ), which retained nanomolar affinity and exhibited an excellent PK profile. Reflecting the good potency and PK profile, orally administrated compound1o 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 compound1o, which represents a promising new chemical tool suitable for the study of SCD1 biology as well as the potential development of novel anticancer therapies.