D. Scott Coffey

The Discovery, Preclinical, and Early Clinical Development of Potent and Selective GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus (LY2881835, LY2922083, and LY2922470)

The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet β-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.

Substrate acidities and conversion times for reactions of amides with di-tert-butyl bicarbonate

Abstract The conversion time tor 4-dimethylaminopyndine catalysed reaction of amides with di- tert -butyl dicarbonate varies dramatically with substrate acidity. The pK a s in DMSO of some amides are determined to support correlation of reactivity with substrate acidity. Particularly acidic substrates, such as 4-thiazolidinone, readily react with a variety of dialkyl dicarbonates. Less acidic substrates react with Boc 2 O but other dialkyl dicarbonates decompose preferentially.

Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm

Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25. On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5 (LY3000328) was selected for clinical development.

Chapter 6.1 Six-membered ring systems: Pyridines and benzo derivatives

Publisher Summary This chapter describes six-membered ring systems particularly pyridines and benzo derivatives. Pyridines and their benzo-derivatives have played an important role in the synthesis of biologically active synthetic and natural substances. As a result, the construction of this molecular architecture has attracted the attention of a diverse array of synthetic methodologies.Transition metal catalysis, radical reactions, and cycloaddition chemistry-based methods have been developed for the construction of this important ring system. Several strategies for pyridine synthesis involving cycloaddition reactions have been reported. Zhu and co-workers have disclosed full details of their ammonium chloride-promoted four-component synthesis of fused pyridines. Intermolecular cycloaddition strategies have also been used successfully. Moody and co-workers have reported the synthesis of a core piece of the thiopeptide antibiotics through a cycloaddition—for example, 2-azadiene and 2-thiazolyl dienophile were submitted to microwave heating for 15 minutes. The substituted pyridine product was isolated in modest yield.