Heteroarylamide smoothened inhibitors: Discovery of N-[2,4-dimethyl-5-(1-methylimidazol-4-yl)phenyl]-4-(2-pyridylmethoxy)benzamide (AZD8542) and N-[5-(1H-imidazol-2-yl)-2,4-dimethyl-phenyl]-4-(2-pyridylmethoxy) benzamide (AZD7254)

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Heteroarylamide smoothened inhibitors: Discovery of N-[2,4-dimethyl-5-(1-methylimidazol-4-yl)phenyl]-4-(2-pyridylmethoxy)benzamide (AZD8542) and N-[5-(1H-imidazol-2-yl)-2,4-dimethyl-phenyl]-4-(2-pyridylmethoxy) benzamide (AZD7254)

机译：杂芳基胺平滑抑制剂：发现N- [2,4-二甲基-5-（1-甲基-5-（1-甲基咪唑-4-基）苯基] -4-（2-吡啶基甲氧基）苯甲酰胺（AZD8542）和N- [5-（1H-咪唑 -2-y1）-2,4-二甲基 - 苯基] -4-（2-吡啶基甲氧基）苯甲酰胺（AZD7254）

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Aberrant hedgehog (Hh) pathway signaling is implicated in multiple cancer types and targeting the Smoothened (SMO) receptor, a key protein of the Hh pathway, has proven effective in treating metastasized basal cell carcinoma. Our lead optimization effort focused on a series of heteroarylamides. We observed that a methyl substitution ortho to the heteroaryl groups on an aniline core significantly improved the potency of this series of compounds. These findings predated the availability of SMO crystal structure in 2013. Here we retrospectively applied quantum mechanics calculations to demonstrate the o-Me substitution favors the bioactive conformation by inducing a dihedral twist between the heteroaryl rings and the core aniline. The o-Me also makes favorable hydrophobic interactions with key residue side chains in the binding pocket. From this effort, two compounds (AZD8542 and AZD7254) showed excellent pharmacokinetics across multiple preclinical species and demonstrated in vivo activity in abrogating the Hh paracrine pathway as well as anti- tumor effects.

机译：异常刺猬（HH）途径信号传递涉及多种癌症类型并靶向平滑的（SMO）受体，HH途径的关键蛋白质，已被证明是有效治疗转移的基础细胞癌。我们的铅优化努力专注于一系列杂芳基芳基。我们观察到苯胺核心对杂芳基的甲基取代邻羟基替酯显着提高了这一系列化合物的效力。这些发现达到了2013年的Smo晶体结构的可用性。在这里，我们回顾性地应用了量子力学计算，以证明通过诱导杂芳基环和核苯胺之间的二偏捻扭曲来替代生物活性构象。 O-ME还具有良好的疏水相互作用与粘合口袋中的钥匙残留侧链。从这种努力来看，两种化合物（AZD8542和AZD7254）在多种临床前物种上显示出优异的药代动力学，并在亚邻旁静脉途径以及抗肿瘤效应中进行了体内活性。

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《Bioorganic and medicinal chemistry》 |2020年第2期|共11页
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1. Heteroarylamide smoothened inhibitors: Discovery of N-[2,4-dimethyl-5-(1-methylimidazol-4-yl)phenyl]-4-(2-pyridylmethoxy)benzamide (AZD8542) and N-[5-(1H-imidazol-2-yl)-2,4-dimethyl-phenyl]-4-(2-pyridylmethoxy) benzamide (AZD7254) [J] . Bioorganic and medicinal chemistry . 2020,第2期

机译：杂芳基胺平滑抑制剂：发现N- [2,4-二甲基-5-（1-甲基-5-（1-甲基咪唑-4-基）苯基] -4-（2-吡啶基甲氧基）苯甲酰胺（AZD8542）和N- [5-（1H-咪唑 -2-y1）-2,4-二甲基 - 苯基] -4-（2-吡啶基甲氧基）苯甲酰胺（AZD7254）
2. Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl) phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor [J] . Liang Qianmao, Chen Yongfei, Yu Kailin, European Journal of Medicinal Chemistry: Chimie Therapeutique . 2017,第期

机译：发现N-（3-（5 - （（3-丙基-4-（吗啉-4-羰基）苯基）氨基）-1-甲基-6-氧代-1,6-二氢吡啶-3-Y1）-2 - 甲基苯基）-4-（叔丁基）苯甲酰胺（CHMFL-BTK-01）作为高选择性不可逆的Bruton的酪氨酸激酶（BTK）抑制剂
3. Crystal structures of N-[(4-phenyl-thia-zol-2-yl)carbamo-thio-yl]benzamide and N-{[4-(4-bromo-phen-yl)thia-zol-2-yl]carbamo-thio-yl}benzamide from synchrotron X-ray diffraction [J] . Acta Crystallographica Section E: Crystallographic Communications . 2016,第9期

机译：N-[（4-苯基-噻唑-2-基）氨基甲硫基-氨基]苯甲酰胺和N-{[4-（4-溴-苯基-苯基）噻唑-2-基]的晶体结构同步加速器X射线衍射的氨基甲硫基基苯甲酰胺
4. Synthesis of 4-[(2-chloroethanimidamido) methyl --N- (prop-2-yn-1-yl) benzamide, a possible in vivo activity probe of DDAH-like enzymes [D] . Ratz, Patrick. 2015

机译：DDAH样酶的体内活性探针4-[（2-氯乙亚胺嘧啶基）甲基-N-（prop-2-yn-1-yl）苯甲酰胺的合成
5. Crystal structures of N-(4-phenylthiazol-2-yl)carbamothioylbenzamide and N-{4-(4-bromophenyl)thiazol-2-ylcarbamothioyl}benzamide from synchrotron X-ray diffraction [O] . Ekaterina S. Gantimurova, Alexander S. Bunev, Kristina Yu. Talina, 2016

机译：N-（4-苯基噻唑-2-基）氨基甲硫基基苯甲酰胺和N-{4-（4-溴邻苯基）噻唑-2-基氨基甲硫基基}苯甲酰胺的晶体结构
6. Crystal structures of N-[(4-phenylthiazol-2-yl)carbamothioyl]benzamide and N-{[4-(4-bromophenyl)thiazol-2-yl]carbamothioyl}benzamide from synchrotron X-ray diffraction [O] . Ekaterina S. Gantimurova, Alexander S. Bunev, Kristina Yu. Talina, 2016

机译：同步辐射X射线衍射的N - [（4-苯基噻唑-2-基）氨基甲酰基]苯甲酰胺和N - {[4-（4-溴苯基）噻唑-2-基]氨基甲酰基}苯甲酰胺的晶体结构

Heteroarylamide smoothened inhibitors: Discovery of N-[2,4-dimethyl-5-(1-methylimidazol-4-yl)phenyl]-4-(2-pyridylmethoxy)benzamide (AZD8542) and N-[5-(1H-imidazol-2-yl)-2,4-dimethyl-phenyl]-4-(2-pyridylmethoxy) benzamide (AZD7254)

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