INCB9471

Expansion of Investigational Areas for CCR5-Targeted Therapies

The therapeutic potential of targeting CCR5 extends beyond HIV infection due to its involvement in immune and inflammatory responses. Research is actively exploring the utility of CCR5 antagonists in a range of conditions where chemokine signaling plays a critical role.

One significant area of expansion is cancer therapy. Preclinical studies have indicated that CCR5 inhibition can influence tumor growth, invasion, and metastasis in various cancer types, including liver, pancreatic, breast, and colorectal cancers. mdpi.complos.orgaacrjournals.org CCR5 antagonists are being investigated for their ability to modulate the tumor microenvironment and enhance the effects of immunotherapy. mdpi.comaacrjournals.org

Inflammatory and autoimmune diseases represent another key area of investigation. CCR5 is involved in the recruitment of immune cells to sites of inflammation, making its antagonists potential therapeutic agents for conditions like multiple sclerosis and graft-versus-host disease. frontiersin.orgfrontiersin.orgnih.gov

Furthermore, research is exploring the neuroprotective and recovery-enhancing effects of CCR5 antagonists in the context of stroke. Preclinical systematic reviews and meta-analyses of animal models of stroke have suggested that CCR5 antagonists may reduce infarct volume and improve behavioral outcomes. researchgate.netelifesciences.org

Hypercytokinemia diseases, including severe infections like COVID-19, have also been considered as potential targets for CCR5 blockade, given the role of chemokines in driving excessive inflammatory responses. justia.com

Advanced Structure-Guided Drug Design for Next-Generation CCR5 Inhibitors

The development of more potent, selective, and effective CCR5 inhibitors relies heavily on advanced structure-guided drug design approaches. The availability of structural information, particularly the crystal structure of CCR5 in complex with antagonists like maraviroc (PDB ID: 4MBS), has been instrumental in enabling structure-based design efforts. scirp.orgtandfonline.comacs.org

These advanced approaches utilize computational techniques such as pharmacophore modeling, virtual screening, molecular docking, and molecular dynamics simulations to identify novel chemical scaffolds and optimize existing ones for improved binding affinity and pharmacological properties. scirp.orgtandfonline.comacs.orgresearchgate.netscirp.org Structure-based pharmacophore models are derived from the detailed interactions between the receptor and known ligands, allowing for the virtual screening of large chemical libraries to find potential new inhibitors. scirp.orgscirp.org Molecular docking predicts the binding orientation and affinity of compounds within the CCR5 binding site, while molecular dynamics simulations provide insights into the stability of the receptor-ligand complex and the dynamic nature of their interactions. scirp.orgtandfonline.comscirp.org

INCB9471 has been included as a reference compound in studies validating structure-based pharmacophore models aimed at discovering novel CCR5 inhibitors. scirp.orgscirp.org This underscores its relevance as a known, potent CCR5 antagonist used to benchmark and refine computational drug design strategies for identifying next-generation compounds with potentially improved characteristics. The goal of these efforts is to overcome limitations observed with earlier CCR5 inhibitors and develop compounds with enhanced efficacy, selectivity, and pharmacokinetic profiles for various indications. scirp.orgtandfonline.comscirp.org

Development and Application of Refined Preclinical Models for CCR5 Research

Refined preclinical models are crucial for accurately evaluating the potential efficacy of CCR5 antagonists in various disease settings and for understanding the complex roles of CCR5 signaling in vivo. The development and application of these models are ongoing to better recapitulate human disease pathology and predict clinical outcomes.

In HIV research, humanized mouse models that can be infected with HIV-1 and develop a disease similar to human AIDS have become valuable tools for evaluating CCR5-targeted therapies. nih.govnih.gov These models allow for the assessment of the impact of CCR5 blockade on viral entry and replication in a living system with a human immune component. nih.govnih.gov

For other investigational areas like stroke and cancer, specific animal models are employed and continuously refined. Stroke models in rodents, for instance, are used to measure the effect of CCR5 antagonists on infarct size and neurological deficits, with ongoing efforts to improve their alignment with clinical trial parameters, such as using clinically relevant sexes, ages, and comorbidities. researchgate.netelifesciences.org Mouse models of various cancers are used to study the impact of CCR5 inhibition on tumor growth, metastasis, and the immune microenvironment. mdpi.complos.orgaacrjournals.org

Preclinical models are also essential for investigating the role of CCR5 and its ligands in inflammatory conditions, including those associated with metabolic diseases like obesity and diabetes, using rodent models to study hypersensitivity and inflammation. mdpi.com

While specific detailed data on the application of refined preclinical models solely for this compound in these emerging areas is limited in the search results, its classification as a CCR5 antagonist that underwent preclinical evaluation nih.gov implies its study in relevant in vivo systems during its development phase. Furthermore, its inclusion in lists of CCR5 inhibitors evaluated in preclinical studies plos.org highlights its contribution to the broader understanding of how this class of compounds behaves in biological systems, informing the design and use of refined models for future CCR5 antagonist research.

Q. What is the synthetic pathway for INCB9471, and how do structural modifications influence its activity?

this compound is synthesized through a multi-step process involving indane ring modifications. Key steps include:

• Introduction of hydroxyl or methoxy groups at the indane 2-position to enhance CCR5 binding affinity.
• Coupling of the piperazinyl-piperidine core (intermediate 16 ) with the indane moiety via alkylation and Boc deprotection .
• Final conjugation with 4,6-dimethylpyrimidine-5-carboxylic acid to yield this compound (22a ). Rationale: Methoxy groups showed minimal activity improvement, while ethyl substitution at the indane ring significantly boosted antiviral potency .

Q. What are the key pharmacokinetic (PK) parameters of this compound in preclinical models?

this compound exhibits low systemic clearance (rat: 4.1 mL/min/kg; dog: 7.5 mL/min/kg), high volume of distribution (rat: 5.7 L/kg; dog: 4.1 L/kg), and excellent oral bioavailability (rat: 100%; dog: 95%) . Protein binding-adjusted IC90 for antiviral activity is ~60 nM (16% free fraction in human serum) .

Q. Which in vitro assays are used to evaluate this compound’s anti-HIV activity?

• MIP-1β binding assays : Measure CCR5 receptor affinity (IC90 = 9 nM for R5 HIV-1 subtypes) .
• Chemotaxis inhibition : Assess blockade of monocyte migration induced by CCR5 ligands .
• Viral inhibition : Peripheral blood mononuclear cell (PBMC) models infected with diverse R5 HIV-1 strains (IC90 range: 0.2–3.8 nM) .

Q. How does protein binding affect this compound’s antiviral efficacy?

this compound’s free fraction in human serum (16%) necessitates adjusting in vitro IC90 values (~60 nM) to account for protein binding. This adjustment ensures accurate translation of potency to in vivo efficacy .

Advanced Research Questions

Q. How can researchers resolve contradictions in structure-activity relationship (SAR) data during CCR5 antagonist optimization?

Example: Methoxy substitution at the indane 2-position (21a ) showed minimal antiviral improvement, while ethyl substitution (22a ) achieved sub-nanomolar activity. Methodological strategies include:

• Iterative synthesis : Test analogs with incremental structural changes (e.g., alkyl chain length).
• Binding kinetics : Compare association/dissociation rates (e.g., this compound’s slow dissociation enhances target engagement) .
• Mutagenesis studies : Identify critical CCR5 residues (e.g., transmembrane domains) for ligand interaction .

Q. What methodological considerations are critical when designing clinical trials for CCR5 antagonists like this compound?

• Patient stratification : Enroll subjects with R5-tropic HIV-1 (exclude X4-tropic via tropism assays) .
• Dosing optimization : Leverage PK/PD modeling to align trough concentrations with protein binding-adjusted IC90 .
• Resistance monitoring : Use site-directed mutagenesis to track viral escape mutations (e.g., V3 loop changes) .

Q. What strategies address potential drug resistance with this compound in HIV treatment?

• Allosteric inhibition : this compound binds noncompetitively to CCR5, reducing overlap with maraviroc’s binding site .
• Combination therapy : Pair with reverse transcriptase inhibitors to limit resistance emergence.
• Preclinical profiling : Test against clinical isolates with known resistance to other CCR5 antagonists (e.g., vicriviroc) .

Q. How do enantiomeric properties of this compound impact its pharmacological profile?

this compound exists as a 1:1 mixture of enantiomers, resolvable via chiral HPLC. Crystallization with acid confirms stereochemical stability, ensuring consistent target engagement .

Methodological Guidance

• SAR Analysis : Use radioligand competition assays and PBMC-based viral inhibition to prioritize analogs .
• PK/PD Translation : Adjust in vitro IC90 values for protein binding and validate in animal models (e.g., rat/dog bioavailability studies) .
• Clinical Trial Design : Apply FINER criteria (Feasible, Novel, Ethical, Relevant) and PICO frameworks for patient selection .