Discovery of a potent, orally available dual CysLT1 and CysLT2 antagonist with dicarboxylic acid

Itadani, Satoshi; Takahashi, Shinya; Ima, Masaki; Sekiguchi, Tetsuya; Egashira, Hiromu; Matsumura, Naoya; Inoue, Atsuto; Yonetomi, Yasuo; Fujita, Manabu; Nakayama, Y.; Takeuchi, Jun

doi:10.1016/j.bmc.2015.03.011

Cited by 8 publications

(6 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As shown in Table , the PK profile of 1 was very poor, and its bioavailability was only 1.5% in rats . However, further modification resulted in 4-(3-(carboxymethyl)-4-{( E )-2-[4-(4-phenoxybutoxy)phenyl]vinyl}-1 H -indol-1-yl)butanoic acid ( 2 , ONO-4310321), which had a significantly improved PK profile in rats . Compound 2 demonstrated a reduction in bronchoconstriction in a dose-dependent manner and complete inhibition at an oral dose of 10 mg/kg in a CysLT 1 -dependent guinea pig bronchoconstriction model.…”

Section: Introductionmentioning

confidence: 94%

“…The indole-3-acetic acid derivative 2 was previously reported. 29 Table 2 shows that indole-1-acetic acid derivative 3, an isomer, is a more potent dual antagonist, with IC 50 values of 1.5 and 6.0 nM against hCysLT 1 and hCysLT 2 , respectively. In addition, both compounds 2 and 3 were orally administered 1 h before LTD 4 challenge at 1 mg/kg, and compound 3 showed potent in vivo efficacy (97% inhibition of bronchoconstriction) compared to compound 2 (48% inhibition).…”

Section: ■ Introductionmentioning

confidence: 98%

“…28 However, further modification resulted in 4-(3-(carboxymethyl)-4-{(E)-2-[4-(4-phenoxybutoxy)phenyl]-vinyl}-1H-indol-1-yl)butanoic acid (2, ONO-4310321), which had a significantly improved PK profile in rats. 29 Compound 2 demonstrated a reduction in bronchoconstriction in a dosedependent manner and complete inhibition at an oral dose of 10 mg/kg in a CysLT 1 -dependent guinea pig bronchoconstric- ■ RESULTS AND DISCUSSION Lead Optimization. The isomer of the core indole ring was initially investigated.…”

Section: ■ Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Discovery of Gemilukast (ONO-6950), a Dual CysLT₁ and CysLT₂ Antagonist As a Therapeutic Agent for Asthma

Itadani¹,

Yashiro²,

Sekiguchi³

et al. 2015

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

An orally active dual CysLT1 and CysLT2 antagonist possessing a distinctive structure which consists of triple bond and dicarboxylic acid moieties is described. Gemilukast (ONO-6950) was generated via isomerization of the core indole and the incorporation of a triple bond into a lead compound. Gemilukast exhibited antagonist activities with IC50 values of 1.7 and 25 nM against human CysLT1 and human CysLT2, respectively, and potent efficacy at an oral dose of 0.1 mg/kg given 24 h before LTD4 challenge in a CysLT1-dependent guinea pig asthmatic model. In addition, gemilukast dose-dependently reduced LTC4-induced bronchoconstriction in both CysLT1- and CysLT2-dependent guinea pig asthmatic models, and it reduced antigen-induced constriction of isolated human bronchi. Gemilukast is currently being evaluated in phase II trials for the treatment of asthma.

show abstract

Section: Introductionmentioning

confidence: 94%

Section: ■ Introductionmentioning

confidence: 98%

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of Gemilukast (ONO-6950), a Dual CysLT₁ and CysLT₂ Antagonist As a Therapeutic Agent for Asthma

Itadani¹,

Yashiro²,

Sekiguchi³

et al. 2015

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…To understand the mechanism of ligand selectivity, we performed docking of 18 derivatives of the common 3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid scaffold 30,31 with a large spectrum of CysLT 1 R/CysLT 2 R selectivity (Supplementary Table 3). Docking models of the most selective compounds in this structure-activity relationship (SAR) series 30 , cpd 13e (1,800-fold selective for CysLT 1 R) and cpd 15b (200-fold selective for CysLT 2 R), are shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors

et al. 2019

View full text Add to dashboard Cite

Cysteinyl leukotriene G protein-coupled receptors CysLT1 and CysLT2 regulate pro-inflammatory responses associated with allergic disorders. While selective inhibition of CysLT1R has been used for treating asthma and associated diseases for over two decades, CysLT2R has recently started to emerge as a potential drug target against atopic asthma, brain injury and central nervous system disorders, as well as several types of cancer. Here, we describe four crystal structures of CysLT2R in complex with three dual CysLT1R/CysLT2R antagonists. The reported structures together with the results of comprehensive mutagenesis and computer modeling studies shed light on molecular determinants of CysLTR ligand selectivity and specific effects of disease-related single nucleotide variants.

show abstract

“…An agent was developed as a dual antagonist of CysLT 1 R and CysLT 2 R, named BAYu9773, but it showed poor potency and selectivity for these receptors in human tissues . More dual antagonists are also under development .…”

Section: Therapeutic Interventions: Cys‐lt Biosynthesis Blockers and mentioning

confidence: 99%

Cysteinyl Leukotrienes and Their Receptors: Emerging Therapeutic Targets in Central Nervous System Disorders

et al. 2016

View full text Add to dashboard Cite

Cysteinyl leukotrienes are a group of the inflammatory lipid molecules well known as mediators of inflammatory signaling in the allergic diseases. Although they are traditionally known for their role in allergic asthma, allergic rhinitis, and others, recent advances in the field of biomedical research highlighted the role of these inflammatory mediators in a broader range of diseases such as in the inflammation associated with the central nervous system (CNS) disorders, vascular inflammation (atherosclerotic), and in cancer. Among the CNS diseases, they, along with their synthesis precursor enzyme 5-lipoxygenase and their receptors, have been shown to be associated with brain injury, Multiple sclerosis, Alzheimer's disease, Parkinson's disease, brain ischemia, epilepsy, and others. However, a lot more remains elusive as the research in these areas is emerging and only a little has been discovered. Herein, through this review, we first provided a general up-to-date information on the synthesis pathway and the receptors for the molecules. Next, we summarized the current findings on their role in the brain disorders, with an insight given to the future perspectives.

show abstract

Discovery of a potent, orally available dual CysLT1 and CysLT2 antagonist with dicarboxylic acid

Cited by 8 publications

References 36 publications

Discovery of Gemilukast (ONO-6950), a Dual CysLT₁ and CysLT₂ Antagonist As a Therapeutic Agent for Asthma

Discovery of Gemilukast (ONO-6950), a Dual CysLT₁ and CysLT₂ Antagonist As a Therapeutic Agent for Asthma

Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors

Cysteinyl Leukotrienes and Their Receptors: Emerging Therapeutic Targets in Central Nervous System Disorders

Contact Info

Product

Resources

About

Discovery of a potent, orally available dual CysLT1 and CysLT2 antagonist with dicarboxylic acid

Cited by 8 publications

References 36 publications

Discovery of Gemilukast (ONO-6950), a Dual CysLT1 and CysLT2 Antagonist As a Therapeutic Agent for Asthma

Discovery of Gemilukast (ONO-6950), a Dual CysLT1 and CysLT2 Antagonist As a Therapeutic Agent for Asthma

Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors

Cysteinyl Leukotrienes and Their Receptors: Emerging Therapeutic Targets in Central Nervous System Disorders

Contact Info

Product

Resources

About

Discovery of Gemilukast (ONO-6950), a Dual CysLT₁ and CysLT₂ Antagonist As a Therapeutic Agent for Asthma

Discovery of Gemilukast (ONO-6950), a Dual CysLT₁ and CysLT₂ Antagonist As a Therapeutic Agent for Asthma