当前位置：
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-02-16 , DOI: 10.1021/acs.jmedchem.3c02248
Valerie W Shurtleff 1 , Mark E Layton 1 , Craig A Parish 2 , James J Perkins 1 , John D Schreier 1 , Yunyi Wang 1 , Gregory C Adam 1 , Nadine Alvarez 3 , Soheila Bahmanjah 2 , Carolyn M Bahnck-Teets 1 , Christopher W Boyce 1 , Christine Burlein 1 , Tamara D Cabalu 1 , Brian T Campbell 1 , Steven S Carroll 1 , Wonsuk Chang 2 , Manuel de Lera Ruiz 1 , Enriko Dolgov 3 , John F Fay 1 , Nicholas G Fox 2 , Shih Lin Goh 1 , Timothy J Hartingh 1 , Danielle M Hurzy 1 , Michael J Kelly 1 , Daniel J Klein 1 , Franca-Maria Klingler 4 , Harini Krishnamurthy 1 , Shalley Kudalkar 1 , Todd W Mayhood 2 , Philip M McKenna 1 , Edward M Murray 1 , Debbie Nahas 1 , Christopher C Nawrat 1 , Steven Park 3 , Dongming Qian 5 , Anthony J Roecker 1 , Vijeta Sharma 3 , William D Shipe 1 , Jing Su 2 , Robert V Taggart 1 , Quang Truong 2 , Yin Wu 5 , Xiaoyan Zhou 2 , Ningning Zhuang 5 , David S Perlin 3 , David B Olsen 1 , John A Howe 1 , John A McCauley 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-02-16 , DOI: 10.1021/acs.jmedchem.3c02248
Valerie W Shurtleff 1 , Mark E Layton 1 , Craig A Parish 2 , James J Perkins 1 , John D Schreier 1 , Yunyi Wang 1 , Gregory C Adam 1 , Nadine Alvarez 3 , Soheila Bahmanjah 2 , Carolyn M Bahnck-Teets 1 , Christopher W Boyce 1 , Christine Burlein 1 , Tamara D Cabalu 1 , Brian T Campbell 1 , Steven S Carroll 1 , Wonsuk Chang 2 , Manuel de Lera Ruiz 1 , Enriko Dolgov 3 , John F Fay 1 , Nicholas G Fox 2 , Shih Lin Goh 1 , Timothy J Hartingh 1 , Danielle M Hurzy 1 , Michael J Kelly 1 , Daniel J Klein 1 , Franca-Maria Klingler 4 , Harini Krishnamurthy 1 , Shalley Kudalkar 1 , Todd W Mayhood 2 , Philip M McKenna 1 , Edward M Murray 1 , Debbie Nahas 1 , Christopher C Nawrat 1 , Steven Park 3 , Dongming Qian 5 , Anthony J Roecker 1 , Vijeta Sharma 3 , William D Shipe 1 , Jing Su 2 , Robert V Taggart 1 , Quang Truong 2 , Yin Wu 5 , Xiaoyan Zhou 2 , Ningning Zhuang 5 , David S Perlin 3 , David B Olsen 1 , John A Howe 1 , John A McCauley 1
Affiliation
|
As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus’s main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.
中文翻译：
发明 MK-7845，一种采用新型二氟谷氨酰胺模拟物的 SARS-CoV-2 3CL 蛋白酶抑制剂
随着 SARS-CoV-2 的持续传播，需要抗病毒治疗来补充疫苗。该病毒的主要蛋白酶 3CLPro 是一个有吸引力的药物靶标，部分原因是它识别一个独特的切割位点，该位点在 P1 位点具有谷氨酰胺残基，不被人类蛋白酶利用。在此，我们报道了 MK-7845 的发明，这是一种新型可逆共价 3CLPro 抑制剂。虽然迄今为止报道的大多数 SARS-CoV-2 3CLPro 共价抑制剂在 P1 处都包含酰胺作为 Gln 模拟物，但 MK-7845 在该位置带有二氟丁基取代基。SAR 分析和 X 射线晶体学研究表明，该基团与 His163 相互作用，His163 与通常在 P1 处发现的酰胺取代基形成氢键的相同残基。除了有希望的体内疗效和可接受的预计人类剂量且药代动力学未增强外，MK-7845 还表现出良好的溶解度和吸收特性，这可能归因于不寻常的二氟丁基取代基。
更新日期：2024-02-16
中文翻译：
发明 MK-7845，一种采用新型二氟谷氨酰胺模拟物的 SARS-CoV-2 3CL 蛋白酶抑制剂
随着 SARS-CoV-2 的持续传播，需要抗病毒治疗来补充疫苗。该病毒的主要蛋白酶 3CLPro 是一个有吸引力的药物靶标，部分原因是它识别一个独特的切割位点，该位点在 P1 位点具有谷氨酰胺残基，不被人类蛋白酶利用。在此，我们报道了 MK-7845 的发明，这是一种新型可逆共价 3CLPro 抑制剂。虽然迄今为止报道的大多数 SARS-CoV-2 3CLPro 共价抑制剂在 P1 处都包含酰胺作为 Gln 模拟物，但 MK-7845 在该位置带有二氟丁基取代基。SAR 分析和 X 射线晶体学研究表明，该基团与 His163 相互作用，His163 与通常在 P1 处发现的酰胺取代基形成氢键的相同残基。除了有希望的体内疗效和可接受的预计人类剂量且药代动力学未增强外，MK-7845 还表现出良好的溶解度和吸收特性，这可能归因于不寻常的二氟丁基取代基。
京公网安备 11010802027423号