The eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein synthesis by binding the 5' terminal mRNA cap structure. We designed and synthesized a series of novel compounds that display potent binding affinity against eIF4E despite their lack of a ribose moiety, phosphate, and positive charge as present in m7-GMP. The biochemical activity of compound 33 is 95 nM for eIF4E in an SPA binding assay. More importantly, the compound has an IC(50) of 2.5 μM for inhibiting cap-dependent mRNA translation in a rabbit reticular cell extract assay (RRL-IVT). This series of potent, truncated analogues could serve as a promising new starting point toward the design of neutral eIF4E inhibitors with physicochemical properties suitable for cellular activity assessment.

A tandem chain extension-aldol reaction was developed in which beta-keto esters are transformed to alpha-substituted-gamma-keto esters in an efficient zinc-mediated, one-pot reaction. The diastereoselectivity of the reaction ranged from good to excellent with syn stereochemistry observed for beta-keto ester and amide substrates and anti-stereochemistry observed for a beta-keto imide. [reaction: see text]

This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic−pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.

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Herein, we report the lead optimization of amrinone−phenylalanine based GPR142 agonists. Structure− activity relationship studies led to the discovery of aminopyrazole−phenylalanine carboxylic acid 22, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability. Compound 22, together with its orally bioavailable ethyl ester prodrug 23, were found to be suitable for in vivo proof-of-concept studies. Compound 23 displayed good efficacy in a mouse oral glucose tolerance test (OGTT). Compound 22 showed GPR142 dependent stimulation of insulin secretion in isolated mouse islets and demonstrated a statistically significant glucose lowering effect in a mouse model bearing transplanted human islets. KEYWORDS: GPR142 agonist, type 2 diabetes, aminopyrazole−phenylalanine, insulin secretagogue, prodrug, oral glucose tolerance test, human islet transplant G PR142, a new member in the super family of seventransmembrane G-protein-coupled receptors (GPCRs), was first reported in 2003 by Schioth and colleagues, 1 and further characterized by Schaller in 2006. 2 GPR142 is a G qcoupled receptor that was expressed predominantly in pancreatic β-cells. Activation of this receptor triggers an intracellular signal transduction pathway, which ultimately leads to β-cell insulin secretion. Tryptophan was recently identified as an endogenous ligand for GPR142. 3 Activation of the receptor by tryptophan was found to stimulate insulin secretion in isolated mouse islets in both a dose-and a glucosedependent manner and was associated with improved glucose tolerance. 3 These findings suggested that GPR142 plays an important role in regulating insulin secretion and glucose homeostasis. This target was therefore deemed suitable for the discovery of agents for the treatment of type II diabetes with a low associated risk of hypoglycemia.We recently reported the discovery of amrinone−phenylalanine GPR142 agonist 1 4 and the subsequent optimization campaign, which provided 2 for preliminary proof-of-concept studies in rodents. 5 While these compounds were both highly potent in a human inositol phosphate (IP) accumulation assay 6 (EC 50 = 0.090 μM for 1 and EC 50 = 0.058 μM for 2), they both suffered from high in vivo clearance, with rat IV clearance of 3.4 and 5.1 L/h/kg, respectively (Figure 1). Compound 2 was also found to be a strong CYP inhibitor. While replacing the pyridone moiety of 1 with a thiadiazole ring was later discovered to reduce rat clearance, 5 this heterocyclic compound was found to be chemically unstable at physiological pH conditions. Further investigation of this chemical series was therefore warranted to address the above issues and to provide a better tool compound for in vivo proof-of-concept studies.We first investigated the role of the central aromatic ring on potency as summarized in Table 1. The strategy employed was to incorporate different heterocyclic rings at the center of the molecule in order to modulate the overall shape ...