Substituted indole-1-acetic acids as potent and selective CRTh2 antagonists-discovery of AZD1981

Medicinal Chemistry, AstraZeneca R&D Charnwood, Loughborough, Leicestershire LE11 5RH, UK.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 09/2011; 21(21):6288-92. DOI: 10.1016/j.bmcl.2011.08.124
Source: PubMed


Novel indole-3-thio-, 3-sulfonyl- and 3-oxy-aryl-1-acetic acids are reported which are potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). Optimization required maintenance of high CRTh2 potency whilst achieving a concomitant reduction in rates of metabolism, removal of cyp p450 inhibition and minimization of aldose reductase and aldehyde reductase activity. High quality compounds suitable for in vivo studies are highlighted, culminating in the discovery of AZD1981 (22).

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    • "Indeed, the dual thromboxane and CRTh2 receptor antagonist seratrodast has been reported to improve lung function in an 8-week study in a cohort of patients with chronic pulmonary emphysema [15]. AZD1981 is an oral, non-steroidal, CRTh2 receptor antagonist [16] [17] that was well-tolerated in phase I trials and has been studied in asthma patients [18]. The aim of this phase IIa study was to evaluate the efficacy and tolerability of AZD1981 compared with placebo in patients with moderate to severe COPD. "
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    ABSTRACT: To evaluate the efficacy and tolerability of the selective CRTh2 (DP2) receptor antagonist AZD1981 compared with placebo in patients with moderate to severe COPD. In this multicentre, randomised, double-blind, parallel-group, phase IIa study ( identifier: NCT00690482) patients with moderate to severe COPD received either AZD1981 1000 mg twice daily or matching placebo for 4 weeks. Inhaled terbutaline was used as-needed as reliever medication throughout. The co-primary endpoints were change from baseline to end of treatment in pre-bronchodilator forced expiratory volume in 1 s [FEV1] and the Clinical COPD Questionnaire (CCQ). Additional endpoints included other lung function measures, 6-min walk test (6-MWT), COPD symptom score, reliever medication use and tolerability. 118 patients were randomised to treatment (AZD1981 n = 61; placebo n = 57); 83% of patients were male and the mean age was 63 years (range 43-83). There were no significant differences in the mean difference in change from baseline to end of treatment between AZD1981 and placebo for the co-primary endpoints of pre-bronchodilator FEV1 (AZD1981-placebo: -0.015, 95% CI: -0.10 to 0.070; p = 0.72) and CCQ total score (difference: 0.042, 95% CI: -0.21 to 0.30; p = 0.75). Similarly, no differences were observed between treatments for the other outcomes of lung function, COPD symptom score, 6-MWT, BODE index, and use of reliever medication. AZD1981 was well tolerated. There was no beneficial clinical effect of AZD1981, at a dose of 1000 mg twice daily for 4 weeks, in patients with moderate to severe COPD. AZD1981 was well tolerated and no safety concerns were identified.
    Respiratory medicine 07/2013; 107(11). DOI:10.1016/j.rmed.2013.06.006 · 3.09 Impact Factor
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    ABSTRACT: This application claims salts and crystalline forms of a previously disclosed DP2 receptor antagonist (2-[3-[2-(tert-butylsulfanylmethyl)-4-(2,2-dimethylpropanoylamino)phenoxy]-4-methoxy-phenyl]acetic acid (1)). It also claims compositions containing the free acid and its salts, especially the sodium salt and their use in the treatment of inflammatory and respiratory diseases, especially asthma. Notably, the application presents Phase I clinical data on compound (1).
    Expert Opinion on Therapeutic Patents 11/2011; 21(12):1931-6. DOI:10.1517/13543776.2011.636738 · 4.30 Impact Factor
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    ABSTRACT: A series of 2-thienyl-3-substitued indole derivatives (1-11) were synthesized. Their structures were established on the basis of elemental and spectral (IR, 1HNMR and Mass spectral data) studies. All the synthesized compounds have been tested for their antitumor activity against breast cancer cell line (MCF-7) using doxorubicin as a standard drug (IC 50 =2.97 μg/ml). Most of the prepared compounds showed good to 50 moderate antitumor activity. The most potent one was 10b ( IC 50 =2.6 μg/ml). Twelve of the prepared compounds 50 were evaluated for their anti-inflammatory activity (against carrageenan induced oedema in albino rats at a dose of 50 mg/kg body weight using indomethacin at a dose of 25mg/kg body weight as a standard drug) and ulcerogenic effect. Compound 9a exhibited 55.31% inhibition with ulcerogenic activity less than that of indomethacin.
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