Naing Aay

INHIBITORS OF GLUCOSYLCERAMIDE SYNTHASE

Publisher Summary Glycosphingolipids are ubiquitous but poorly understood membrane components. They amass because of defective glycosidases or activator proteins for these glycosidases in several sphingolipid storage disorders. These disorders include Gaucher, Fabry, and Tay-Sachs disease where glucosylceramide, globotriaosylceramide (Gb3), and ganglioside GM2, respectively, accumulate within the affected tissues. Glucosylceramide is the base cerebroside for the majority of glycosphingolipids, including Gb3 and ganglioside GM2. Whereas the roles of these glycosphingolipids in the pathogenesis of sphingolipidoses are well appreciated, the normal physiological roles of glucosylceramide-based glycolipids are less well understood. The means for better understanding these functions is through the selective inhibition of cellular glucosylceramide formation. The search and identification by Radin and co-workers of specific inhibitors of glucosylceramide synthase has provided a widely used tool for understanding the cellular biology of glycosphingolipids. The parent compound, D - threo -1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), has found wide application in this regard. More recently, a series of structurally related homologs that exhibit greater sensitivity and specificity toward the cerebroside synthase have been designed and tested. This chapter describes the discovery, synthesis, and characterization of PDMP and these newer homologs.

Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973)

The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials.

Discovery of a novel class of highly potent, selective, ATP-competitive, and orally bioavailable inhibitors of the mammalian target of rapamycin (mTOR).

A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.

Discovery and characterization of an inhibitor of glucosylceramide synthase.

Targeting glycosphingolipid synthesis has emerged as a novel approach for treating metabolic diseases. 32 (EXEL-0346) represents a new class of glucosylceramide synthase (GCS) inhibitors. This report details the elaboration of hit 8 with the goal of achieving and maintaining maximum GCS inhibition in vivo. 32 inhibited GCS with an IC(50) of 2 nM and achieved maximum hepatic GCS inhibition after four or five daily doses in rodents. Robust improvements in glucose tolerance in DIO mice and ZDF rats were observed after 2 weeks of q.d. dosing. Four weeks of dosing resulted in decreased plasma triglycerides and reduced hepatic fat deposition. Thus, 32 provides insight into the amount of metabolic regulation that can be restored following achievement of maximal target knockdown.