Isoquinoline derivatives as potent CRTH2 receptor antagonists: Synthesis and SAR

Nishikawa-Shimono, Rie; Sekiguchi, Yoshinori; Koami, Takeshi; Kawamura, Madoka; Wakasugi, Daisuke; Watanabe, Kazuhito; Wakahara, Shunichi; Matsumoto, Kayo; Takayama, Tetsuo

doi:10.1016/j.bmcl.2012.03.009

Cited by 12 publications

(3 citation statements)

References 17 publications

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“…However, a dual antagonist of human D prostanoid and CRTh2, AMG 853, has shown no effect on asthma control outcomes in a small trial of patients with moderate-to-severe asthma on ICS 30. Isoquinoline derivatives are also being investigated as potential CRTh2 receptor antagonists 31. It may be argued that, as an add-on anti-inflammatory, the key benefit of CRTh2 receptor antagonists may be in preventing inflammation-driven exacerbations, which could not be properly assessed in either of the short-term trials performed with AZD1981, OC000459, or AMG 853.…”

Section: Discussionmentioning

confidence: 99%

Two Phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma

Kuna¹,

Bjermer²,

Tornling³

2016

DDDT

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BackgroundChemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cell (CRTh2) receptor antagonists is being investigated for asthma.ObjectivesThe aim of this study was to assess the effects of the CRTh2 receptor antagonist, AZD1981 (with/without inhaled corticosteroids [ICSs]), on lung function and asthma control.Patients and methodsAdults aged 18–60 years were enrolled in two randomized, placebo-controlled, parallel-group trials (protocol number: D9830C00003 [study 1, n=209] and protocol number: D9830C00004 [study 2, n=510]). In study 1, patients with stable asthma (forced expiratory volume in 1 second [FEV1]: 65%−110%) were withdrawn from ICS (<400 µg/d) and randomized to AZD1981 1,000 mg twice daily (bid) or placebo. In study 2, patients with uncontrolled asthma (FEV1: 40%−85%) despite ICS therapy (≥500 µg/d) were randomized to 50 mg, 400 mg, or 1,000 mg bid AZD1981 or placebo. The primary efficacy variable for both trials was the change in morning peak expiratory flow after 4 weeks of treatment. Secondary variables included Asthma Control Questionnaire (ACQ-5) scores, FEV1 assessments, safety, and tolerability. In study 2, efficacy was also assessed according to atopic status.ResultsFollowing 4 weeks of treatment, there was a nonsignificant increase in morning peak expiratory flow on AZD1981 1,000 mg bid (9.5 L/min vs placebo, P=0.086 [study 1] and 12 L/min vs placebo, P=0.16 [study 2]). In study 2, all doses of AZD1981 provided significant improvements in ACQ-5 scores (0.26–0.3 units vs placebo, P=0.010–0.022); however, there was no dose–response relationship. Improved ACQ-5 scores and FEV1 were observed in the majority of atopic patients treated with AZD1981. AZD1981 was well tolerated across treatment groups.ConclusionFurther research may be warranted in atopic patients to fully evaluate the clinical efficacy of AZD1981.

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Section: Discussionmentioning

confidence: 99%

Two Phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma

Kuna¹,

Bjermer²,

Tornling³

2016

DDDT

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“…Several potent CRTH2 receptor antagonists, including isoquinoline derivatives (TASP0376377) [ 66 ], substituted indole-1-acetic acids (AZD1981) [ 67 ], and other molecules (OC000459, AM211, setipiprant, ARRY-502, MK-7246) have been synthesized and studied.…”

Section: Clinical Evaluations Of Dp and Crth2 Antagonismmentioning

confidence: 99%

Targeting the PGD2/CRTH2/DP1 Signaling Pathway in Asthma and Allergic Disease: Current Status and Future Perspectives

Kupczyk

Kuna

2017

Drugs

103

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Prostaglandin D2 (PGD2) released by degranulating mast cells is believed to play a key role in orchestrating mechanisms of inflammation in allergies and asthma. The biological effects of PGD2 are mediated by D-prostanoid (DP1), CRTH2 (DP2), and thromboxane prostanoid (TP) receptors. The CRTH2 receptor is involved in induction of migration and activation of T helper type 2 (Th2) lymphocytes, eosinophils, and basophils; up-regulation of adhesion molecules; and promotion of pro-inflammatory Th2-type cytokines (interleukin [IL]-4, 5, 13), whereas the DP receptor is associated with relaxation of smooth muscles, vasodilation, inhibition of cell migration, and apoptosis of eosinophils. A number of CRTH2/PGD2 receptor antagonists have been investigated in asthma and allergic diseases. The CRTH2 antagonist (OC000459) or dual CRTH2 and TP receptor antagonist (ramatroban) were effective in reducing eosinophilia, nasal mucosal swelling, and clinical symptoms of allergic rhinitis, with the latter drug registered for clinical use in this indication. OC000459 and setipiprant reduced the late but not early phase of response in an allergen challenge in atopic asthmatics. In persistent asthma, some molecules induced limited improvement in lung function, quality of life, and asthma symptoms (OC000459, BI671800), but in other trials with AMG 853 and AZ1981 these findings were not confirmed. The clear discrepancy between animal studies and clinical efficacy of CRTH2 antagonism in allergic rhinitis, and lack of efficacy in a general cohort of asthmatics, highlight the issue of patient phenotyping. There is no doubt that the PGD2/CATH2/DP1 pathway plays a key role in allergic inflammation and further studies with selective or combined antagonisms in well defined cohorts of patients are needed.

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“…9,10) In our continuous research focused on identifying an alternative lead class, we took particular note of the carbonyl linker of 1, because the modification of this linker would impact the physicochemical properties of 1. We designed novel CRTH2 antagonists bearing a methylene linker in place of the carbonyl linker, expecting to change the biological profile of this chemotype by changing its physicochemical properties.…”

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Isoquinoline Derivatives as Potent, Selective, and Orally Active CRTH2 Antagonists

Nishikawa-Shimono

Sekiguchi

Kawamura

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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Synthesis and structure-activity relationship of a novel series of isoquinoline CRTH2 antagonists bearing a methylene linker between the isoquinoline and benzamide moieties were described. Optimization focusing on the substituents of the benzamide portion in the right hand part of the molecule led to the identification of TASP0412098 (9l), which is a potent, selective CRTH2 antagonist (binding affinity: IC 50 2.1 nM, functional activity: IC 50 12 nM). Compound 9l, which was orally bioavailable in mice and guinea pigs, showed in vivo efficacy after oral administration in a bronchial asthma model of guinea pigs.Key words CRTH2 antagonist; allergic diseases; isoquinoline; prostaglandin D2The chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) was reported in 2001 as a G protein-coupled receptor for prostaglandin D2 (PGD2). CRTH2 is expressed on eosinophils, basophils, and Th2 cells, and plays an important role in allergic diseases, driving the immunoglobulin E (IgE) response, eosinophilia, and the release of proinflammatory cytokines.1-3) Activation of CRTH2 promotes the release of histamine from basophils and degranulation of eosinophiles.4-6) Thus, a CRTH2 antagonist might be beneficial for a variety of inflammatory diseases. 7,8) Research designed to identify selective CRTH2 antagonists dramatically increased after the discovery that the thromboxane receptor antagonist, ramatroban, which is approved for the treatment of allergic rhinitis, and the anti-inflammatory drug, indomethacin, were found to be CRTH2 antagonists. A large number of structure-activity relationship (SAR) information around the indoleacetic acids have been disclosed.In our previous paper, we reported that the lead generation process and initial SAR study of a novel isoquinoline chemotype of CRTH2 antagonists, led to the identification of compound 1 (binding affinity: IC 50 =19 nM, functional activity: IC 50 =13 nM) as a potent and selective CRTH2 antagonist. 9,10) In our continuous research focused on identifying an alternative lead class, we took particular note of the carbonyl linker of 1, because the modification of this linker would impact the physicochemical properties of 1. We designed novel CRTH2 antagonists bearing a methylene linker in place of the carbonyl linker, expecting to change the biological profile of this chemotype by changing its physicochemical properties. In the present study, we described the synthesis and SAR of isoquinoline CRTH2 antagonists containing a methylene linker, and the preliminary pharmacokinetic and pharmacological profiles of the potent, selective, and orally active CRTH2 antagonist 9l, which is the most potent compound of this class.Chemistry Preparation of isoquinoline derivatives 9a-9u is outlined in Chart 1. The ylide 3, derived from commercially available benzyl bromide 2, was treated with methyl 1-chloroisoquinoline-4-carboxylate in the presence of sodium hexamethyldisilazane, followed by hydrolysis, to give 4 in 58% yield.11) The carboxylic acid 5, prepared by the basic hydro...

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Isoquinoline derivatives as potent CRTH2 receptor antagonists: Synthesis and SAR

Cited by 12 publications

References 17 publications

Two Phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma

Two Phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma

Targeting the PGD2/CRTH2/DP1 Signaling Pathway in Asthma and Allergic Disease: Current Status and Future Perspectives

Isoquinoline Derivatives as Potent, Selective, and Orally Active CRTH2 Antagonists

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