Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ Inhibitors

  • J Med Chem. 2016 Jan 14;59(1):431-47. doi: 10.1021/acs.jmedchem.5b01651.
Youngsook Shin ,  Julia Suchomel ,  Mario Cardozo ,  Jason Duquette ,  Xiao He ,  Kirk Henne ,  Yi-Ling Hu ,  Ron C Kelly ,  John McCarter ,  Lawrence R McGee ,  Julio C Medina ,  Daniela Metz ,  Tisha San Miguel ,  Deanna Mohn ,  Thuy Tran ,  Christine Vissinga ,  Simon Wong ,  Sharon Wannberg ,  Douglas A Whittington  1 ,  John Whoriskey ,  Gang Yu ,  Leeanne Zalameda ,  Xuxia Zhang ,  Timothy D Cushing
Affiliations
  • 1. Department of Therapeutic Discovery, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
PMID: 26652588 DOI: 10.1021/acs.jmedchem.5b01651
Abstract

Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 1 (AM-8508) and 2 (AM-9635), with good pharmacokinetic properties. The compounds inhibit B cell receptor (BCR)-mediated Akt phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compounds which share a benzimidazole bicycle are effective when administered in vivo at unbound concentrations consistent with their in vitro cell potency as a consequence of improved unbound drug concentration with lower unbound clearance. Furthermore, the compounds demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inhibitors 1 and 2 led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH.

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