GLPG3221 / AbbVie, Galapagos - LARVOL DELTA

Scale up of clinical candidates and key intermediates for cystic fibrosis and hepatitis C (ACS-Fall 2023) - "In this talk, we profile two case studies from a 20+ year career at AbbVie that spans work in Discovery, Process, and a dedicated synthesis group. These case studies will focus on the scale up of clinical candidate ABBV-3221 from the Cystic Fibrosis program and ABT-493 for the treatment of HCV."

Clinical • Cystic Fibrosis • Fibrosis • Genetic Disorders • Hepatitis C • Hepatology • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases

Asymmetric synthesis of densely functionalized pyrrolidines via copper-catalyzed [3+2] cycloaddition: Scope, optimization, and application to the scale up of ABBV-3221 (ACS-Sp 2023) - "Herein we describe the identification and optimization of a surprisingly general method to synthesize tetrasubstituted pyrrolidines with up to >20:1 diastereoselectivity and 99% enantioselectivity via asymmetric [3+2] cycloaddition between azomethine ylides and nitroalkenes. Subsequent downstream transformations of the cycloadducts are described that enabled access to versatile intermediates of significant impact to medicinal chemistry programs, and kg-scale campaigns successfully incorporated the methodology into the scale up of C2-corrector compound ABBV-3221 for AbbVie’s cystic fibrosis program."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Novel Correctors and Potentiators Enhance Functional Rescue of CFTR Nonsense Mutation Translational Readthrough. (PubMed, Am J Respir Cell Mol Biol) - "Novel correctors GLPG2222 (C1), GLPG3221 (C2), and potentiator GLPG1837 compare favorably to lumacaftor and ivacaftor in vitro. In G542X/R553X or R1162X/R1162X organoids, enhanced forskolin induced swelling (FIS) was observed with G418+GLPG1837+C1a+C2a although GLPG1837+C1a+C2a alone was sufficient to improve FIS in W1282X/W1282X organoids. Combination of CFTR correctors, potentiators and readthrough compounds augments the functional repair of CFTR nonsense mutations, indicating the potential for novel correctors and potentiators to restore function to truncated W1282X CFTR."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Discovery of ABBV/GLPG-3221, a Potent Corrector of CFTR for the Treatment of Cystic Fibrosis. (PubMed, ACS Med Chem Lett) - "The identification of a pyrrolidine series of CFTR C2 correctors and the structure-activity relationship of this series is described. This work resulted in the discovery and selection of (2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylic acid (ABBV/GLPG-3221), which was advanced to clinical trials."

Journal • CFTR