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首页> 外文会议>Collegium Internationale Allergologicum >LAS 36674, A New Generation of H1 Antihistamines: From Bench to Bedside and Back
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LAS 36674, A New Generation of H1 Antihistamines: From Bench to Bedside and Back

机译：LAS 36674，新一代H1抗组胺药：从长凳到床边和背部

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Background: The objective of our work was to develop potent, selective and long lasting H_1 antihistamines devoid of cardiotoxicity, sedative effects and drug-drug interactions that may be favorably differentiated with respect to the second-generation antihistamines. In this study, we describe the profile of two new H_1 antihistamines named LAS 32928 and LAS 36674. Methods and Results: LAS 32928, an indolylpiperidinyl benzoic acid derivative, with a favorable preclinical profile, was initially selected for clinical development In healthy male volunteers, LAS 32928 (10, 25, and 50 mg administered as an oral suspension during 5 consecutive days) showed a promising efficacy and safety profile, but its development was discontinued due to its short duration of action and elimination half-life. In order to improve the duration of action and phannacokinetic profile of LAS 32928 new indolylpiperidinyl derivatives were synthesized. LAS 36674 was selected as a candidate for development based on its potent and long lasting antihistamine activity in rats, low brain penetration in mice and rats, lack of cardiotoxicity, no significant interaction with CYP450 isoforms and long elimination half-life in rats. Conclusions: LAS 36674 showed an improved preclinical pharmacological and ADME profile compared to its predecessor LAS 32928. LAS 36674 demonstrated a higher efficacy/safety ratio than second-generation antihistamines in preclinical models, suggesting the potential for a superior benefit/risk profile in humans.
机译：背景：我们工作的目的是开发有效，选择性和长期的H_1抗组胺药，其缺乏心脏毒性，镇静效果和药物 - 药物相互作用，这可能是有利地分化的第二代抗组胺药。在这项研究中，我们描述了名为LAS 32928和LAS 36674的两个新的H_1抗组胺瘤的轮廓。方法和结果：LAS 32928，具有有利的临床前型材的吲哚基哌啶基苯甲酸衍生物，最初选择用于健康男性志愿者的临床发育，在连续5天内以口腔悬浮液施用的LAS 32928（10,25和50mg）显示出有希望的疗效和安全性，但由于其短暂的作用和消除半衰期，其开发是停止的。为了改善LAS 32928的动作持续时间和LAS 32928的Phannocokinetic曲线合成。合成了新的吲哚基哌啶基衍生物。基于其大鼠的效力和长期持久的抗组胺药活性，小鼠和大鼠缺乏症状，缺乏心脏毒性，缺乏心脏毒性，LAS 36674作为发展的候选者，缺乏CYP450同种型和大鼠的长期消除半衰期。结论：LAS 36674与其前任LAS 32928相比，LAS 36674显示了一种改进的临床前药理学和Adme曲线。LAS 36674在临床前模型中表现出比第二代抗组胺的效率/安全比更高，表明人类中优越益处/风险概况的潜力。

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