Synthesis of Enantiopure Unnatural Amino Acids by Metallaphotoredox Catalysis.

We describe herein a two-step process for the conversion of serine to a wide array of optically pure unnatural amino acids. This method utilizes a photocatalytic cross-electrophile coupling between a bromoalkyl intermediate and a diverse set of aryl halides to produce artificial analogues of phenylalanine, tryptophan, and histidine. The reaction is tolerant of a broad range of functionalities and can be leveraged toward the scalable synthesis of valuable pharmaceutical scaffolds via flow technology.

Rapid Optimization of Photoredox Reactions for Continuous-Flow Systems Using Microscale Batch Technology.

Photoredox catalysis has emerged as a powerful and versatile platform for the synthesis of complex molecules. While photocatalysis is already broadly used in small-scale batch chemistry across the pharmaceutical sector, recent efforts have focused on performing these transformations in process chemistry due to the inherent challenges of batch photocatalysis on scale. However, translating optimized batch conditions to flow setups is challenging, and a general approach that is rapid, convenient, and inexpensive remains largely elusive.

Discovery of an Orally Efficacious Positive Allosteric Modulator of the Glucagon-like Peptide-1 Receptor.

The identification of LSN3318839, a positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), is described. LSN3318839 increases the potency and efficacy of the weak metabolite GLP-1(9-36)NH to become a full agonist at the GLP-1R and modestly potentiates the activity of the highly potent full-length ligand, GLP-1(7-36)NH. LSN3318839 preferentially enhances G protein-coupled signaling by the GLP-1R over β-arrestin recruitment.

Metallaphotoredox-Catalyzed Cross-Electrophile C-C Coupling of Aliphatic Bromides.

A strategy for the installation of small alkyl fragments onto pharmaceutically relevant aliphatic structures has been established via metallaphotoredox catalysis. Herein, we report that tris(trimethylsilyl)silanol can be employed as an effective halogen abstraction reagent that, in combination with photoredox and nickel catalysis, allows a generic approach to C-C cross-electrophile coupling. In this study, we demonstrate that a variety of aliphatic drug-like groups can be successfully coupled with a number of commercially available small alkyl electrophiles, including methyl tosylate and strained cyclic alkyl bromides.

Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences.

NMR conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines, or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1.

Synthesis of Spirocyclic Pyrazolones by Oxidative C-N Bond Formation.

The two-step synthesis of spirocyclic pyrazolone derivatives from simple and commercially available reagents is described. The unusual reaction of 1,3-dicarbonyls with hydrazines and an iodine-mediated oxidative carbon-nitrogen bond formation, joined in a two-step, one-pot reaction, allows the straightforward synthesis of these spirocycles.

2-Alkoxydihydrocinnamates as PPAR agonists. Activity modulation by the incorporation of phenoxy substituents.

Herein we describe a series of potent and selective PPARgamma agonists with moderate PPARalpha affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound 1b (LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes.

Novel selective and potent 5-HT reuptake inhibitors with 5-HT1D antagonist activity: chemistry and pharmacological evaluation of a series of thienopyran derivatives.

A series of compounds combining the naphthylpiperazine and thienopyran scaffolds has been prepared and evaluated for 5-HT reuptake inhibition with 5-HT1D antagonist activity. The design of these compounds has been based on the 'overlapping type' strategy where two pharmacophores are linked in a single molecule. The resultant dual pharmacological profile has the potential to deliver a more efficient treatment for depression.