Design, Synthesis, and Pharmacological Evaluation of Second-Generation Tetrahydroisoquinoline-Based CXCR4 Antagonists with Favorable ADME Properties

Abstract

CXCR4 is a G-protein-coupled receptor that interacts with its cognate ligand, CXCL12, to synchronize many physiological responses and pathological processes. Disruption of the CXCL12-CXCR4 circuitry by small-molecule antagonists has emerged as a promising strategy for cancer intervention. We previously disclosed a hit-to-lead effort that led to the discovery of a series of tetrahydroisoquinoline-based CXCR4 antagonists exemplified by the lead compound TIQ15. Herein, we describe our medicinal-chemistry efforts toward the redesign of TIQ15 as a result of high mouse-microsomal clearance, potent CYP2D6 inhibition, and poor membrane permeability. Guided by the in vitro ADME data of TIQ15, structural modifications were executed to provide compound 12a, which demonstrated a reduced potential for first-pass metabolism while maintaining CXCR4 potency. Subsequent SAR studies and multiparameter optimization of 12a resulted in the identification of compound 25o, a highly potent, selective, and metabolically stable CXCR4 antagonist possessing good intestinal permeability and low risk of CYP-mediated drug-drug interactions.

Facile titanium(IV) chloride and TBD‐mediated synthesis of N‐aryl‐substituted azacycles from arylhydrazines

“…Tetrahydroisoquinoline and isoindoline are nitrogen‐fused heterocyclic ring structures that exist in many bioactive molecules including natural products and commercially available pharmaceuticals 21 . Thus, the discovery of a novel synthetic method for tetrahydroisoquinoline and isoindoline is valuable for drug discovery, thus this reaction protocol using TiCl 4 and TBD was applied for preparation of nitrogen‐fused heterocyclic ring structures (Table 4).…”

Synthesis and Anti-HIV Activity of a Novel Series of Isoquinoline-Based CXCR4 Antagonists

“…Substitution of the bicyclic heteroaromatic moiety by a partially saturated ring system yielded the tetrahydroisoquinoline derivative 5 (also known as TIQ15, Figure 1 ), which is a highly potent and selective CXCR4 antagonist [ 15 ]. Further optimization yielded compound 6 , which has improved in vitro ADME properties compared to compound 5 [ 16 ]. In contrast to the lower part, the upper tetrahydroquinoline moiety of AMD-11070 has been left relatively unexplored.…”

Probing the Druggablility on the Interface of the Protein–Protein Interaction and Its Allosteric Regulation Mechanism on the Drug Screening for the CXCR4 Homodimer

“…CXCR4 is one of 23 known human chemokine receptors, which plays a key role in leukocyte trafficking, hematopoiesis, organ development and cancer metastases (Zweemer et al, 2014). It was revealed that CXCR4 is associated with more than 23 types of cancers (Wu et al, 2010; Nguyen et al, 2018). CXCR4 and related CC chemokine receptor 5 (CCR5) are not only the key regulators of signal transduction, but also involve in the entry of HIV-1 virus as coreceptors of HIV-1 into leukocytes (Shaik et al, 2019).…”