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Discovery of (3-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone (AZD1979), a Melanin Concentrating Hormone Receptor 1 (MCHr1) Antagonist with Favorable Physicochemical Properties
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-02-05 00:00:00 , DOI: 10.1021/acs.jmedchem.5b01654 Anders Johansson 1 , Christian Löfberg 1 , Madeleine Antonsson 1 , Sverker von Unge 1 , Martin A. Hayes 1 , Robert Judkins 1 , Karolina Ploj 1 , Lambertus Benthem 1 , Daniel Lindén 1 , Peter Brodin 1 , Marie Wennerberg 1 , Marléne Fredenwall 1 , Lanna Li 1 , Joachim Persson 1 , Rolf Bergman 1 , Anna Pettersen 1 , Peter Gennemark 1 , Anders Hogner 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-02-05 00:00:00 , DOI: 10.1021/acs.jmedchem.5b01654 Anders Johansson 1 , Christian Löfberg 1 , Madeleine Antonsson 1 , Sverker von Unge 1 , Martin A. Hayes 1 , Robert Judkins 1 , Karolina Ploj 1 , Lambertus Benthem 1 , Daniel Lindén 1 , Peter Brodin 1 , Marie Wennerberg 1 , Marléne Fredenwall 1 , Lanna Li 1 , Joachim Persson 1 , Rolf Bergman 1 , Anna Pettersen 1 , Peter Gennemark 1 , Anders Hogner 1
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A novel series of melanin concentrating hormone receptor 1 (MCHr1) antagonists were the starting point for a drug discovery program that culminated in the discovery of 103 (AZD1979). The lead optimization program was conducted with a focus on reducing lipophilicity and understanding the physicochemical properties governing CNS exposure and undesired off-target pharmacology such as hERG interactions. An integrated approach was taken where the key assay was ex vivo receptor occupancy in mice. The candidate compound 103 displayed appropriate lipophilicity for a CNS indication and showed excellent permeability with no efflux. Preclinical GLP toxicology and safety pharmacology studies were without major findings and 103 was taken into clinical trials.
中文翻译：
发现（3-（4-（2-Oxa-6-氮杂螺[3.3]庚-6-基甲基）苯氧基）氮杂环丁烷-1-基）（5-（4-甲氧基苯基）-1,3,4-恶二唑- 2-基）甲酮（AZD1979），具有良好理化特性的黑色素浓缩激素受体1（MCHr1）拮抗剂。
一系列新的黑色素浓缩激素受体1（MCHr1）拮抗剂是药物发现计划的起点，该计划最终发现了103（AZD1979）。进行前导优化程序的重点是降低亲脂性并了解控制CNS暴露和不期望的脱靶药理作用（例如hERG相互作用）的理化性质。采取了一种综合方法，其中关键测定是小鼠体内离体受体的占有率。候选化合物103对于CNS适应症表现出适当的亲脂性，并且显示出优异的渗透性而没有外排。临床前GLP毒理学和安全药理学研究无重大发现，有103例被纳入临床试验。
更新日期：2016-02-05
中文翻译：
发现（3-（4-（2-Oxa-6-氮杂螺[3.3]庚-6-基甲基）苯氧基）氮杂环丁烷-1-基）（5-（4-甲氧基苯基）-1,3,4-恶二唑- 2-基）甲酮（AZD1979），具有良好理化特性的黑色素浓缩激素受体1（MCHr1）拮抗剂。
一系列新的黑色素浓缩激素受体1（MCHr1）拮抗剂是药物发现计划的起点，该计划最终发现了103（AZD1979）。进行前导优化程序的重点是降低亲脂性并了解控制CNS暴露和不期望的脱靶药理作用（例如hERG相互作用）的理化性质。采取了一种综合方法，其中关键测定是小鼠体内离体受体的占有率。候选化合物103对于CNS适应症表现出适当的亲脂性，并且显示出优异的渗透性而没有外排。临床前GLP毒理学和安全药理学研究无重大发现，有103例被纳入临床试验。
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