5,6,7,8-Tetrahydro-1,6-naphthyridine Derivatives as Potent HIV-1-Integrase-Allosteric-Site Inhibitors

  • J Med Chem. 2019 Feb 14;62(3):1348-1361. doi: 10.1021/acs.jmedchem.8b01473.
Kevin M Peese ,  Christopher W Allard ,  Timothy Connolly ,  Barry L Johnson ,  Chen Li ,  Manoj Patel ,  Margaret E Sorensen ,  Michael A Walker ,  Nicholas A Meanwell ,  Brian McAuliffe ,  Beatrice Minassian ,  Mark Krystal ,  Dawn D Parker ,  Hal A Lewis ,  Kevin Kish ,  Ping Zhang ,  Robert T Nolte  1 ,  Jean Simmermacher ,  Susan Jenkins ,  Christopher Cianci ,  B Narasimhulu Naidu
Affiliations
  • 1. Protein Cellular and Structural Sciences , GlaxoSmithKline , 1250 South Collegeville Rd. , Collegeville , Pennsylvania 19426 , United States.
PMID: 30609350 DOI: 10.1021/acs.jmedchem.8b01473
Abstract

A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for Antiviral chemotherapy, was prepared and screened for activity against HIV-1 Infection in Cell Culture. Small molecules that bind within the LEDGF/p75-binding site promote aberrant multimerization of the integrase enzyme and are of significant interest as HIV-1-replication inhibitors. Structure-activity-relationship studies and rat pharmacokinetic studies of lead compounds are presented.