Structure–Kinetic Relationships—An Overlooked Parameter in Hit-to-Lead Optimization: A Case of Cyclopentylamines as Chemokine Receptor 2 Antagonists

Abstract

Preclinical models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a critical role of the chemokine receptor 2 (CCR2) and chemokine ligand 2 (CCL2). However, one of the biggest problems of high-affinity inhibitors of CCR2 is their lack of efficacy in clinical trials. We report a new approach for the design of high-affinity and long-residence-time CCR2 antagonists. We developed a new competition association assay for CCR2, which allows us to investigate the relation of the structure of the ligand and its receptor residence time [i.e., structure-kinetic relationship (SKR)] next to a traditional structure-affinity relationship (SAR). By applying combined knowledge of SAR and SKR, we were able to re-evaluate the hit-to-lead process of cyclopentylamines as CCR2 antagonists. Affinity-based optimization yielded compound 1 with good binding (Ki = 6.8 nM) but very short residence time (2.4 min). However, when the optimization was also based on residence time, the hit-to-lead process yielded compound 22a, a new high-affinity CCR2 antagonist (3.6 nM), with a residence time of 135 min.

Structure–Affinity Relationships (SARs) and Structure–Kinetics Relationships (SKRs) of Kv11.1 Blockers

“…Table 2) compared to the dofetilide series (Table 1). However, when the benzoylpiperidine was replaced by benzoylpiperazine (15), the K i value was drastically increased to 5418 ± 374 nM and its association rate was substantially decreased to (2.7 ± 0.6) × 10 −4 nM −1 ·min −1 . Distinct from the variations in affinities and association rates, all E-4031 derivatives displayed comparably short RTs between 2.0 ± 0.5 (14) and 2.9 ± 0.8 min (16) at the K v 11.1 channel.…”

What Do Structures Tell Us About Chemokine Receptor Function and Antagonism?

“…This imposes constraints on potency, residence time (139), selectivity, and toxicity parameters of chemokine receptor drug candidates that by far exceed typical ranges for other targets. In combination with the inherently poor druggability of the receptor:chemokine interfaces, it creates a conflict between pharmacodynamics (PD) and pharmacokinetics (PK) requirements and makes discovery and development of successful competitive small molecule chemokine receptor antagonists a daunting task.…”

“…As for other GPCRs, important properties of drug candidates include target residence time for ensuring adequate receptor occupancy and receptor selectivity for minimizing off-target effects (22, 139). However chemokine receptors pose additional challenges that may be less problematic for other GPCRs.…”

Kinetic and structural insights into the binding of histone deacetylase 1 and 2 (HDAC1, 2) inhibitors

“…Alternatively, prolonged target engagement across multiple HDAC isoforms may drive mechanism-based toxicity, such as thrombocytopenia, and decrease the therapeutic window. 10 By developing a structure-kinetic relationship (SKR) 11 for inhibitors towards HDAC1 and HDAC2, the development of kinetically different binding parameters for each isoform will define optimal target engagement to maximize the PD response and therapeutic index.…”