Discovery and evaluation of a novel monocyclic series of CXCR2 antagonists

Austin, Rupert P.; Bennion, Colin; Bonnert, Roger V.; Cheema, Lal; Cook, Anthony R.; Cox, Rhona J.; Ebden, Mark R.; Gaw, Allan; Grime, Ken; Meghani, Premji; Nicholls, David J.; Phillips, Caroline; Smith, Neal; Steele, John W.; Stonehouse, Jeffrey P.

doi:10.1016/j.bmcl.2015.01.067

Cited by 14 publications

(12 citation statements)

References 21 publications

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“…To design a CXCR2 antagonist with improved human PK properties, we needed to both improve the bioavailability of AZD8309 and increase the effective half-life. The former was achieved by designing a monocyclic series of sulfamides with increased solubility (Austin et al, 2015). The latter was tackled by examining the data presented in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…2B, most likely due to a combination of poor distribution properties for these acidic molecules and lipophilicity playing a "canceling out" role through impacting both PPB and affinity for tissue. Given the observation that increasing acidity is related to increasing potency and PPB (Austin et al, 2015), the proposed strategy in the CXCR2 program was to increase acidity to increase both parameters while reducing logD 7.4 to obtain better metabolic stability. Using a CL prediction method incorporating drugbinding terms and a regression line method (Grime and Riley, 2006;Sohlenius-Sternbeck et al, 2012), a simple simulation demonstrated the general PK strategy for the program (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In the AstraZeneca CXCR2 drug discovery program, the acidity of the molecules was shown to be an important parameter for increasing both CXCR2 receptor binding and PPB (Austin et al, 2015). We outline the approaches taken and lessons learned from early CXCR2 clinical drug candidates and describe the preclinical data analysis that led to a strategy for achieving PK half-lives commensurate with once and twice daily dosing, ultimately resulting in the improved clinical drug candidates N-(2-[(2,3-difluorobenzyl)sulfanyl]-6-{[(2R,3S)-3,4dihydroxy-2-butanyl]oxy}-4-pyrimidinyl)-1-azetidinesulfonamide (AZD5069) and AZD4721.…”

Section: Introductionmentioning

confidence: 99%

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Plasma Protein Binding as an Optimizable Parameter for Acidic Drugs

2019

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The low volume of distribution associated with acidic molecules means that clearance (CL) must also be very low to achieve an effective half-life commensurate with once or twice daily dosing. Plasma protein binding (PPB) should not usually be considered a parameter for optimization, but in the particular case of acidic molecules, raising the PPB above a certain level can result in distribution volume becoming a constant low value equal to the distribution volume of albumin while acting to reduce CL through restricting hepatic and renal access of unbound drug. Thus effective half-life can be increased. Here we detail the approaches and lessons learned at AstraZeneca during the optimization of acidic CXC chemokine receptor 2 (CXCR2) antagonists for the oral drug treatment of inflammatory diseases, resulting in discovery and clinical testing of N-[2-[(2,3-difluorophenyl)methylsulfanyl]-6-[(2R,3S)-3,4-dihydroxybutan-2-yl]oxypyrimidin-4-yl]azetidine-1-sulfonamide (AZD5069) and AZD4721, orally bioavailable acidic molecules with PPB of <1%, human hepatocyte intrinsic clearance values <5 ml/min per 10 6 cells and predicted human volume of distribution at steady state (V ss ) <0.3 l/kg, resulting in effective half-lives in humans of 4 and 17 hours, respectively. SIGNIFICANCE STATEMENTProvided that the pharmacologic potency is high enough, modulation of plasma protein binding can form part of a viable strategy in drug discovery to optimize the effective half-life of drug candidates in humans. 865

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Plasma Protein Binding as an Optimizable Parameter for Acidic Drugs

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“…A new series of monocyclic CXCR2 antagonists with improved solubility and good pharmacokinetic profiles is under investigation [69].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Non-eosinophilic Asthma Endotypes

Agache

2015

Curr Treat Options Allergy

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“…Inhibition of the CXCR2 chemokine receptor, therefore, represents an attractive strategy for the treatment of inflammatory disorders. To support a programme aimed at developing CXCR2 antagonists, AZD5069 ( 1 ) (Figure ) was identified as a potent, orally active small molecule that demonstrated selective reversible antagonism of human CXCR2. To investigate the pharmacokinetic and metabolism profile of the compound, the preparations of tritium and carbon‐14‐labelled AZD5069 were conducted.…”

Section: Introductionmentioning

confidence: 99%

Syntheses of a radiolabelled CXCR2 antagonist AZD5069 and its major human metabolite

Hickey

Allen

Caffrey

et al. 2016

J. Label Compd. Radiopharm

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The CXCR2 antagonist AZD5069 has been synthesized in tritium and carbon-14-labelled forms. [(3) H]AZD5069 was prepared via reductive dehalogenation of an iodinated precursor with tritium gas to provide material with a specific activity of 25.1 Ci/mmol. [(14) C]AZD5069 was labelled in the pyrimidine ring from [(14) C]thiourea in an overall radiochemical yield of 18%. In addition, a synthetic route to the major metabolite of AZD5069 was developed. The synthesis of this metabolite was achieved from AZD5069 using a chemoselective Lindgren-Pinnick reaction in order to minimize oxidation of the sulphide group.

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Discovery and evaluation of a novel monocyclic series of CXCR2 antagonists

Cited by 14 publications

References 21 publications

Plasma Protein Binding as an Optimizable Parameter for Acidic Drugs

Plasma Protein Binding as an Optimizable Parameter for Acidic Drugs

Non-eosinophilic Asthma Endotypes

Syntheses of a radiolabelled CXCR2 antagonist AZD5069 and its major human metabolite

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