AZD2098

Chemokine receptor antagonists with α1-adrenergic receptor blocker activity

Objectives: Chemokine receptor antagonists are being explored for their therapeutic potential in various disease processes. As the chemokine (C-C motif) receptor 2 (CCR2) antagonist RS504393 is known to compete with ligand binding to α1-adrenoceptors, we tested a panel of 10 CCR antagonists for interactions with α1-adrenoceptors to evaluate potential cardiovascular activities and side-effect profiles. Methods: The PRESTO-Tango β-arrestin recruitment assay was utilized to test whether the CCR antagonists interfere with α1b-AR activation upon stimulation with phenylephrine. Pressure myography with isolated rat resistance arteries was employed to assess their effects on phenylephrine-induced vasoconstriction. The following antagonists were tested: CCR1-BX471, BX513, BI639667; CCR2-RS504393, INCB3284; CCR3-SB328437; and CCR4-AZD2098, and C021; CCR5-Maraviroc; CCR10-BI6901. The pan-α1-adrenoceptor antagonist prazosin was used as control. Results: Among the CCR antagonists tested, RS504393, BX513, and C021 inhibited phenylephrine-induced β-arrestin recruitment to α1b-adrenoceptor and phenylephrine-induced vasoconstriction. While RS504393 functioned as a competitive α1-adrenoceptor blocker, BX513 and C021 functioned as noncompetitive α1-adrenoceptor antagonists in both assay systems. Furthermore, RS504393, BX513, and C021 dose-dependently dilated arteries that were fully preconstricted with phenylephrine. Conclusions: Our data suggest that CCR antagonists should be screened for cross-reactivity with α1-adrenoceptors to exclude potential adverse cardiovascular effects when used as anti inflammatory drugs.

CCL17 exerts neuroprotection through activation of CCR4/mTORC2 axis in microglia after subarachnoid haemorrhage in rats

Background and purpose: C-C motif chemokine ligand 17 (CCL17) presents an important role in immune regulation, which is critical in the pathophysiology of brain injury after subarachnoid haemorrhage (SAH). There is rare evidence to illustrate the function of CCL17 towards SAH. In this study, we try to reveal the therapeutic effects of CCL17 and its underlying mechanism in rat SAH model.
Methods: SAH rat models were assigned to receive recombinant CCL17 (rCCL17) or phosphate buffer saline (PBS). AZD2098 and JR-AB2-011 were applied to investigate the C-C motif chemokine receptor 4 (CCR4)/mammalian target of rapamycin complex 2 (mTORC2) axis in CCL17-mediated neuroprotection. To elucidate the underlying mechanism, the in vitro kinase assay was performed in primary microglia. Microglial-specific Rictor knockdown was administered via intracerebroventricular injection of adenovirus-associated virus. Brain water content, short-term neurobehavioural evaluation, western blot analysis, quantitative RT-PCR and histological staining were performed.
Results: The expression of CCL17 was increased and secreted from neurons after oxyhaemoglobin stimulation. Exogenous rCCL17 significantly alleviated neuronal apoptosis, and alleviated short-term neurofunction after SAH in rats. In addition, rCCL17 increased M2-like polarisation of microglia in rats post-SAH and in primary microglia culture. The neuroprotection of rCCL17 was abolished via inhibition of either CCR4 or mTORC2.
Conclusion: CCL17 activated the CCR4/mTORC2 axis in microglia, which can alleviate SAH-induced neurological deficits by promoting M2-like polarisation of microglia.

Hyperoside inhibits proinflammatory cytokines in human lung epithelial cells infected with Mycoplasma pneumoniae

Mycoplasma pneumoniae pneumonia (MPP) is the most common respiratory infection in young children and its incidence has increased worldwide. In this study, high expression of chemokine ligand 5 (CCL5) was observed in the serum of MPP patients, and its expression was positively correlated to DNA of M. pneumoniae (MP-DNA). In vitro, M. pneumoniae (MP) infection to A549 cells induced the expression of CCL5, chemokines receptor 4 (CCR4), nuclear factor-κB (NF-κB) nuclear protein, and phosphorylation of NF-κB-p65 (p-NF-κB-p65), whereas NF-κB cytoplasmic protein was decreased. On the contrary, treatment of hyperoside counteracted the induction of MP infection and promoted the proliferation of MP-infected A549 cells. Similarly, MP-induced IL-8 and TNF-α production was also markedly reduced by hyperoside. And CCR4 inhibitor AZD2098 had a better effect than hyperoside. In addition, CCL5 recombinant protein inhibited the effect of hyperoside to promote IL-8 and TNF-α production and CCR4 expression. These results indicated that CCL5 may be involved in the progression of MPP, and hyperoside was beneficial for MPP probably through CCL5-CCR4 interactions, which may provide a potential effective therapy for MPP.

Charity gives life to languishing drugs

As part of an innovative profit-sharing program, Cancer Research UK has been partnering with industry to bring sidelined and novel drugs into clinical trials for cancer. In December, the charity announced its ninth such partnership since 2007-an agreement with AstraZeneca to take the experimental asthma drug AZD2098 into a clinical trial for kidney cancer.

Discovery of AZD-2098 and AZD-1678, Two Potent and Bioavailable CCR4 Receptor Antagonists

N-(5-Bromo-3-methoxypyrazin-2-yl)-5-chlorothiophene-2-sulfonamide 1 was identified as a hit in a CCR4 receptor antagonist high-throughput screen (HTS) of a subset of the AstraZeneca compound bank. As a hit with a lead-like profile, it was an excellent starting point for a CCR4 receptor antagonist program and enabled the rapid progression through the Lead Identification and Lead Optimization phases resulting in the discovery of two bioavailable CCR4 receptor antagonist candidate drugs.