AZD8329 / AstraZeneca - LARVOL DELTA

Design, synthesis, and pharmacological evaluation of novel PROTAC degraders targeting 11β-HSD1 for metabolic disease intervention. (PubMed, Bioorg Chem) - "A series of bifunctional molecules were synthesized based on CRBN- and VHL-recruiting ligands, with AZD8329-derived warheads linked via polyethylene glycol chains...Molecular dynamics simulations revealed that the H-3-V ternary complex exhibited superior binding energy compared to less active analogs. Collectively, this study introduces a novel chemical modality for 11β-HSD1 modulation and lays the groundwork for future therapeutic development targeting metabolic diseases via protein degradation."

Journal • Diabetes • Genetic Disorders • Inflammation • Metabolic Disorders • Obesity • Targeted Protein Degradation • Type 2 Diabetes Mellitus • CRBN

Pharmacological inhibition of hydroxysteroid 11-beta dehydrogenase type 1 (11-βHSD1) after myocardial infarction preserves cardiac function in a translational mini-pig model. (PubMed, Br J Pharmacol) - "Pharmacological inhibition of 11-ßHSD1 after MI prevents deterioration of cardiac function and detrimental remodelling. 11-ßHSD1 inhibitors have safely reached Phase 2 clinical trials in diabetes and dementia, and could be repurposed as an addition to standard care after MI to prevent the development of heart failure."

Journal • Preclinical • Alzheimer's Disease • Cardiovascular • CNS Disorders • Congestive Heart Failure • Dementia • Diabetes • Heart Failure • Inflammation • Metabolic Disorders • Myocardial Infarction

De Novo Crystal Structure Determination from Machine Learned Chemical Shifts. (PubMed, J Am Chem Soc) - "Solid-state NMR chemical shifts can be used to solve this problem, but they are limited by the high computational cost associated with crystal structure prediction methods and density functional theory chemical shift calculations. Here, we successfully determine the crystal structures of ampicillin, piroxicam, cocaine, and two polymorphs of the drug molecule AZD8329 using on-the-fly generated machine-learned isotropic chemical shifts to directly guide a Monte Carlo-based structure determination process starting from a random gas-phase conformation."

Journal

To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of oral administration of AZD8329 (AZ8329) (clinicaltrials.gov) - AZ; P1; N=45

Diabetes

Chemical shift based NMR crystallography of molecular crystals (ACS-Sp 2020) - "The figure shows the full three-dimensional structure determined by NMR for a powder sample of the drug molecule AZD8329. The positional errors are visualized as ORTEP plots drawn at the 90% probability level."