Structure activity relationships of fused bicyclic and urea derivatives of spirocyclic compounds as potent CCR1 antagonists

Hossain, Nafizal; Mensonides-Harsema, Marguérite; Cooper, Martin; Eriksson, Tomas; Ivanova, Svetlana; Bergström, Lena

doi:10.1016/j.bmcl.2013.11.062

Cited by 8 publications

(3 citation statements)

References 18 publications

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“…The formation of disulfides [41] is a possible mechanism; however, the enzyme environment in the proximity of warhead does not contain components that should support oxidation or radical-like reaction mechanisms. Based on previous publications, [42][43][44][45][46][47] we investigated alternative reaction mechanisms for the covalent labelling of thione compounds. In the first step of the proposed mechanism -after the Cys145-His41 proton transfer -the thiolate form of cysteine [23] attacks the central carbon atom of the benzXazole ring in the thione form, whereupon either a CÀ N or a CÀ O bond is broken and the ring is opened.…”

Section: Covalent Binding By Quantum Mechanical Calculations On a Mod...mentioning

confidence: 99%

Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones

Mihalovits,

Kollár,

Bajusz

et al. 2023

ChemPhysChem

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Heterocyclic thiones have recently been identified as reversible covalent warheads, consistent with their mild electrophilic nature. Little is known so far about their mechanism of action in labelling nucleophilic sidechains, especially cysteines. The vast number of tractable cysteines promotes a wide range of target proteins to examine; however, our focus was put on functional cysteines. We chose the main protease of SARS‐CoV‐2 harboring Cys145 at the active site that is a structurally characterized and clinically validated target of covalent inhibitors. We screened an in‐house, cysteine‐targeting covalent inhibitor library which resulted in several covalent fragment hits with benzoxazole, benzothiazole and benzimidazole cores. Thione derivatives and Michael acceptors were selected for further investigations with the objective of exploring the mechanism of inhibition of the thiones and using the thoroughly characterized Michael acceptors for benchmarking our studies. Classical and hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations were carried out that revealed a new mechanism of covalent cysteine labelling by thione derivatives, which was supported by QM and free energy calculations and by a wide range of experimental results. Our study shows that the molecular recognition step plays a crucial role in the overall binding of both sets of molecules.

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Section: Covalent Binding By Quantum Mechanical Calculations On a Mod...mentioning

confidence: 99%

Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones

Mihalovits,

Kollár,

Bajusz

et al. 2023

ChemPhysChem

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“…Further information on chemokine receptors including CCR1 can be found at the International Union of Basic and Clinical Pharmacology (IUPHAR)/BPS website (http://www.guidetopharmacology.org/). Scientists from Berlex (now Bayer HealthCare Pharmaceuticals) provided the first small molecule antagonist for CCR1 in 1998 (Hesselgesser et al, 1998), and since then, numerous inhibitors have been identified (Gladue et al, 2003;Vallet et al, 2007;Merritt et al, 2009;Kerstjens et al, 2010;Dairaghi et al, 2011;2012;Gardner et al, 2013;Pennell et al, 2013;Hossain et al, 2014). To date, six compounds targeting CCR1 have undergone clinical trials (Table 1) for multiple sclerosis, rheumatoid arthritis and chronic obstructive pulmonary disease (Gladue et al, 2010;Karash and Gilchrist, 2011).…”

Section: Introductionmentioning

confidence: 99%

Identifying bias in CCR1 antagonists using radiolabelled binding, receptor internalization, β‐arrestin translocation and chemotaxis assays

Gilchrist

Gauntner

Fazzini

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEInvestigators have suggested that the chemokine receptor CCR1 plays a role in multiple myeloma. Studies using antisense and neutralizing antibodies to CCR1 showed that down-regulation of the receptor altered disease progression in a mouse model. More recently, experiments utilizing scid mice injected with human myeloma cells demonstrated that the CCR1 antagonist BX471 reduced osteolytic lesions, while the CCR1 antagonist MLN-3897 prevented myeloma cell adhesion to osteoclasts. However, information is limited regarding the pharmacology of CCR1 antagonists in myeloma cells. EXPERIMENTAL APPROACHWe compared several well-studied CCR1 antagonists including AZD4818, BX471, CCX354, CP-481715, MLN-3897 and PS899877 for their ability to inhibit binding of [ 125 I]-CCL3 in vitro using membranes prepared from RPMI 8226 cells, a human multiple myeloma cell line that endogenously expresses CCR1. In addition, antagonists were assessed for their ability to modulate CCL3-mediated internalization of CCR1 and CCL3-mediated cell migration using RPMI 8226 cells. As many GPCRs signal through β-arrestin-dependent pathways that are separate and distinct from those driven by G-proteins, we also evaluated the compounds for their ability to alter β-arrestin translocation. KEY RESULTSThere were clear differences between the CCR1 antagonists in their ability to inhibit CCL3 binding to myeloma cells, as well as in their ability to inhibit G-protein-dependent and -independent functional responses. CONCLUSIONS AND IMPLICATIONSOur studies demonstrate that tissue phenotype seems to be relevant with regards to CCR1. Moreover, it appears that for CCR1 antagonists, inhibition of β-arrestin translocation is not necessarily linked to chemotaxis or receptor internalization. AbbreviationsEA, enzyme acceptor; MM, multiple myeloma; MIP-1α, macrophage inflammatory protein-1α; PEN, penicillin; STREP, streptomycin BJP British Journal of Pharmacology

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“…Recently, reported cryogenic-electron microscopy (cryo-EM) structures of the CCR1–G i complex bound to different CCL15 truncations provided the first structural insights into CCR1 activation by endogenous chemokines . Since the early 2000s, CCR1 is known to play an important role in rheumatoid arthritis (RA), multiple sclerosis (MS), Alzheimer’s disease (AD), and multiple myeloma (MM). − More recent publications also suggest CCR1 as a potential drug target for the treatment of systemic fungal infections, obesity-associated cancer, Behcet’s disease, and COVID-19. − This high therapeutic potential has prompted intense efforts in the development of small-molecule antagonists of CCR1. ,,− Due to highly promising results from preclinical studies, several small-molecule CCR1 antagonists, including BX-471 ( 1 , also referred to as BAY 86-5047 or ZK-811752) and BMS-817399 ( 2 ) entered clinical trials (see Figure ). However, none of the clinically evaluated CCR1 antagonists have reached market approval so far, which is mainly attributed to their limited therapeutic efficacy. , For example, BX-471 ( 1 ) failed to show efficacy in a phase II clinical trial in patients with relapsing remitting MS .…”

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confidence: 99%

Fluorophore-Labeled Pyrrolones Targeting the Intracellular Allosteric Binding Site of the Chemokine Receptor CCR1

Toy,

Huber,

Lee

et al. 2024

ACS Pharmacol. Transl. Sci.

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In this study, we describe the structure-based development of the first fluorescent ligands targeting the intracellular allosteric binding site (IABS) of the CC chemokine receptor type 1 (CCR1), a G protein-coupled receptor (GPCR) that has been pursued as a drug target in inflammation and immune diseases. Starting from previously reported intracellular allosteric modulators of CCR1, tetramethylrhodamine (TAMRA)labeled ligands were designed, synthesized, and tested for their suitability as fluorescent tracers to probe binding to the IABS of CCR1. In the course of these studies, we developed LT166 (12) as a highly versatile fluorescent CCR1 ligand, enabling cell-free as well as cellular NanoBRET-based binding studies in a nonradioactive and high-throughput manner. Besides the detection of intracellular allosteric ligands by direct competition with 12, we were also able to monitor the binding of extracellular antagonists due to their positive cooperative binding with 12. Thereby, we provide a straightforward and nonradioactive method to easily distinguish between ligands binding to the IABS of CCR1 and extracellular negative modulators. Further, we applied 12 for the identification of novel chemotypes for intracellular CCR1 inhibition that feature high binding selectivity for CCR1 over CCR2. For one of the newly identified intracellular CCR1 ligands (i.e., 23), we were able to show CCR1 over CCR2 selectivity also on a functional level and demonstrated that this compound inhibits basal β-arrestin recruitment to CCR1, thereby acting as an inverse agonist. Thus, our fluorescent CCR1 ligand 12 represents a highly promising tool for future studies of CCR1-targeted pharmacology and drug discovery.

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Structure activity relationships of fused bicyclic and urea derivatives of spirocyclic compounds as potent CCR1 antagonists

Cited by 8 publications

References 18 publications

Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones

Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones

Identifying bias in CCR1 antagonists using radiolabelled binding, receptor internalization, β‐arrestin translocation and chemotaxis assays

Fluorophore-Labeled Pyrrolones Targeting the Intracellular Allosteric Binding Site of the Chemokine Receptor CCR1

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