Discovery of Clinical Candidate (5-(3-(4-Chlorophenoxy)prop-1-yn-1-yl)-3-hydroxypicolinoyl)glycine, an Orally Bioavailable Prolyl Hydroxylase Inhibitor for the Treatment of Anemia

Zhang, Xiaojin; Lei, Yonghua; Hu, Tianhan; Wu, Yue; Li, Zhihong; Jiang, Zhensheng; Yang, Changyong; Zhang, Lianshan; You, Qidong

doi:10.1021/acs.jmedchem.0c01161

Cited by 18 publications

(14 citation statements)

References 34 publications

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“…Table 1 shows cisplatin protocols in mice reported in publications in 2020/2021. Nephrotoxicity [42][43][44] was by far the most frequently studied toxicity, followed by neurotoxicity [45][46][47], ototoxicity [16,48,49], gonadotoxicity [50][51][52][53], gastrointestinal toxicity [54][55][56], muscle wasting [57][58][59] and anemia [60]. A MEDILINE/PubMed search, using keywords "cisplatin","mouse","toxicity" was conducted in February 2021.…”

Section: Cisplatin Mouse Modelsmentioning

confidence: 99%

Cisplatin Mouse Models: Treatment, Toxicity and Translatability

Perše

2021

Biomedicines

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Cisplatin is one of the most widely used chemotherapeutic drugs in the treatment of a wide range of pediatric and adult malignances. However, it has various side effects which limit its use. Cisplatin mouse models are widely used in studies investigating cisplatin therapeutic and toxic effects. However, despite numerous promising results, no significant improvement in treatment outcome has been achieved in humans. There are many drawbacks in the currently used cisplatin protocols in mice. In the paper, the most characterized cisplatin protocols are summarized together with weaknesses that need to be improved in future studies, including hydration and supportive care. As demonstrated, mice respond to cisplatin treatment in similar ways to humans. The paper thus aims to illustrate the complexity of cisplatin side effects (nephrotoxicity, gastrointestinal toxicity, neurotoxicity, ototoxicity and myelotoxicity) and the interconnectedness and interdependence of pathomechanisms among tissues and organs in a dose- and time-dependent manner. The paper offers knowledge that can help design future studies more efficiently and interpret study outcomes more critically. If we want to understand molecular mechanisms and find therapeutic agents that would have a potential benefit in clinics, we need to change our approach and start to treat animals as patients and not as tools.

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Section: Cisplatin Mouse Modelsmentioning

confidence: 99%

Cisplatin Mouse Models: Treatment, Toxicity and Translatability

Perše

2021

Biomedicines

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“…The bioisosteric replacement of a benzene ring that is fused to another ring in circumstances where it acts as a rigid spacer has been investigated as part of the design of a new series of alkynyl-containing inhibitors of prolyl hydroxylase (PHD) based on roxadustat ( 107a ) as the prototype. Roxadustat ( 107a ) was approved in China in 2018 as a first-in-class PHD inhibitor for the treatment of anemia resulting from chronic kidney disease (CKD) . While the initial analogue 107b showed improved in vitro inhibitory activity toward PHD2, further optimization resulted in the identification of 107c as the most active compound, both in vitro and in vivo , and this compound has been progressed into clinical studies as a potential oral therapy for the treatment of CKD-related anemia (Table ).…”

Section: Bioisosteric Replacement Of Fused Phenyl Ringsmentioning

confidence: 93%

“…Roxadustat (107a) was approved in China in 2018 as a firstin-class PHD inhibitor for the treatment of anemia resulting from chronic kidney disease (CKD). 191 While the initial analogue 107b showed improved in vitro inhibitory activity toward PHD2, further optimization resulted in the identification of 107c as the most active compound, both in vitro and in vivo, and this compound has been progressed into clinical studies as a potential oral therapy for the treatment of CKDrelated anemia (Table 88). Compound 107c displayed oral bioavailability of 56% and 54% in rats and dogs, respectively, with desirable safety profiles even at the high dose of 200 mg/ kg in these animals and was efficacious in a cisplatin-induced mouse model of anemia at a dose of 25 mg/kg PO.…”

Section: Bioisosteric Replacement Ofmentioning

confidence: 99%

“…Compound 107c displayed oral bioavailability of 56% and 54% in rats and dogs, respectively, with desirable safety profiles even at the high dose of 200 mg/ kg in these animals and was efficacious in a cisplatin-induced mouse model of anemia at a dose of 25 mg/kg PO. 191 As part of an effort to introduce structural diversity into the CNS penetrant PI3Kγ inhibitor 108a, the benzothiazole ring was deannelated to generate 108b, where the alkyne linker was designed to preserve the topological relationship between the pyridine and core thiazole rings (Table 89). 192 This specific transform preserved both the inhibitory potency and kinase isoform selectivity of 108a.…”

Section: Bioisosteric Replacement Ofmentioning

confidence: 99%

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Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

2021

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The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity in drug design either as a pharmacophore or as a scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at the beginning of the 21st century highlighted the indiscriminate deployment of phenyl rings as an important contributor to the poor physicochemical properties of advanced molecules, which limited their prospects of being developed into effective drugs. This Perspective deliberates on the design and applications of bioisosteric replacements for a phenyl ring that have provided practical solutions to a range of developability problems frequently encountered in lead optimization campaigns. While the effect of phenyl ring replacements on compound properties is contextual in nature, bioisosteric substitution can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG channel.

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“…Over the past two decades, the development of PHD inhibitors to activate the HIF-2 pathway for the treatment of renal anemia has attracted widespread attention. − PHD inhibitors reduce the degradation of HIF-α by inhibiting the hydroxylation modification activity of PHD, thereby increasing the levels of HIF complexes . However, PHD inhibitors increase the levels of the three HIF subtypes with poor selectivity for HIF-2α .…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Potent and Orally Bioavailable Hypoxia-Inducible Factor 2α (HIF-2α) Agonist and Its Synergistic Therapy with Prolyl Hydroxylase Inhibitors for the Treatment of Renal Anemia

Yang

et al. 2021

J. Med. Chem.

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Activation of hypoxia-inducible factor 2 (HIF-2) has emerged as a potent renal anemia treatment strategy. Here, the benzisothiazole derivative 26 was discovered as a novel HIF-2α agonist, which first demonstrated nanomolar activity (EC 50 = 490 nM, E max = 349.2%) in the luciferase reporter gene assay. Molecular dynamics simulations indicated that 26 could allosterically enhance HIF-2 dimerization. Furthermore, compound 26 had a good pharmacokinetic profile (the oral bioavailability in rats was 41.38%) and an in vivo safety profile (the LD 50 in mice was greater than 708 mg•kg −1 ). In the in vivo efficacy assays, the combination of 26 and the prolyl hydroxylase inhibitor, AKB-6548, was confirmed for the first time to synergistically increase the plasma erythropoietin level in mice (from 260 to 2296 pg•mL −1 ) and alleviate zebrafish anemia induced by doxorubicin. These results provide new insights for HIF-2α agonists and the treatment of renal anemia.

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Discovery of Clinical Candidate (5-(3-(4-Chlorophenoxy)prop-1-yn-1-yl)-3-hydroxypicolinoyl)glycine, an Orally Bioavailable Prolyl Hydroxylase Inhibitor for the Treatment of Anemia

Cited by 18 publications

References 34 publications

Cisplatin Mouse Models: Treatment, Toxicity and Translatability

Cisplatin Mouse Models: Treatment, Toxicity and Translatability

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

Discovery of a Potent and Orally Bioavailable Hypoxia-Inducible Factor 2α (HIF-2α) Agonist and Its Synergistic Therapy with Prolyl Hydroxylase Inhibitors for the Treatment of Renal Anemia

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