2. Academic Validation
  3. Synthesis and Evaluation of Novel Tetrahydronaphthyridine CXCR4 Antagonists with Improved Drug-like Profiles

Synthesis and Evaluation of Novel Tetrahydronaphthyridine CXCR4 Antagonists with Improved Drug-like Profiles

  • J Med Chem. 2022 Mar 10;65(5):4058-4084. doi: 10.1021/acs.jmedchem.1c01564.
Edgars Jecs 1,  Yesim A Tahirovic 1,  Robert J Wilson 1,  Eric J Miller 1,  Michelle Kim 1,  Valarie Truax 1,  Huy H Nguyen 1,  Nicholas S Akins 1,  Manohar Saindane 1,  Tao Wang 2,  Chi S Sum 2,  Mary E Cvijic 2,  Gretchen M Schroeder 2,  Samantha L Burton 3 4,  Cynthia A Derdeyn 3 4 5,  Lingjie Xu 6,  Yi Jiang 6,  Lawrence J Wilson 1,  Dennis C Liotta 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Emory University, 1515 Dickey Drive NE, Atlanta, Georgia 30322, United States.
  • 2 Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
  • 3 Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, United States.
  • 4 Emory Vaccine Center, Emory University, Atlanta, Georgia 30322, United States.
  • 5 Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia 30322, United States.
  • 6 Hangzhou Junrui Biotechnology, Hangzhou, Zhejiang 310000, China.
PMID: 35179893 DOI: 10.1021/acs.jmedchem.1c01564
Abstract

Our first-generation CXCR4 Antagonist TIQ15 was rationally modified to improve drug-like properties. Introducing a nitrogen atom into the aromatic portion of the tetrahydroisoquinoline ring led to several heterocyclic variants including the 5,6,7,8-tetrahydro-1,6-naphthyridine series, greatly reducing the inhibition of the CYP 2D6 Enzyme. Compound 12a demonstrated the best overall properties after profiling a series of isomeric tetrahydronaphthyridine analogues in a battery of biochemical assays including CXCR4 antagonism, CYP 2D6 inhibition, metabolic stability, and permeability. The butyl amine side chain of 12a was substituted with various lipophilic groups to improve the permeability. These efforts culminated in the discovery of compound 30 as a potent CXCR4 Antagonist (IC50 = 24 nM) with diminished CYP 2D6 activity, improved PAMPA permeability (309 nm/s), potent inhibition of human immunodeficiency virus entry (IC50 = 7 nM), a cleaner off-target in vitro safety profile, lower human ether a-go-go-related gene channel activity, and higher oral bioavailability in mice (% FPO = 27) compared to AMD11070 and TIQ15.

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