Major Aspartyl Peptidase 1 inhibitors(University of Charles)(Major Aspartyl Peptidase 1 inhibitors(University of Charles))

概要

基本信息

药物类型

小分子化药

别名

Compound 25(University of Charles)

靶点

ASRGL1

作用方式

抑制剂

作用机制

ASRGL1 inhibitors(asparaginase and isoaspartyl peptidase 1 inhibitors)

治疗领域

感染其他疾病

在研适应症

隐球菌病

非在研适应症-

原研机构

University of Charles

在研机构

University of Charles

非在研机构-

权益机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

关联

100 项与 Major Aspartyl Peptidase 1 inhibitors(University of Charles) 相关的临床结果

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100 项与 Major Aspartyl Peptidase 1 inhibitors(University of Charles) 相关的转化医学

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100 项与 Major Aspartyl Peptidase 1 inhibitors(University of Charles) 相关的专利（医药）

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1

项与 Major Aspartyl Peptidase 1 inhibitors(University of Charles) 相关的文献（医药）

Journal of Medicinal Chemistry

On-Resin Assembly of Macrocyclic Inhibitors of Cryptococcus neoformans May1: A Pathway to Potent Antifungal Agents

Article

作者: Majer, Pavel ; Brynda, Jiří ; Tloušt’ová, Eva ; Craik, Charles S. ; Madhani, Hiten D. ; Boucher, Michael J. ; Hadzima, Martin ; Verner, Václav ; Hájek, Miroslav ; Řezáč, Jan ; Konvalinka, Jan ; Starková, Jana ; Pecina, Adam ; Trajhan, Filip ; Kryštůfek, Robin ; Chalupský, Karel ; Šácha, Pavel ; Dvořáková, Alexandra

Macrocyclic inhibitors have emerged as a privileged scaffold in medicinal chemistry, offering enhanced selectivity, stability, and pharmacokinetic profiles compared to their linear counterparts. Here, we describe a novel, on-resin macrocyclization strategy for the synthesis of potent inhibitors targeting the secreted protease Major Aspartyl Peptidase 1 in Cryptococcus neoformans, a pathogen responsible for life-threatening fungal infections. By employing diverse aliphatic linkers and statine-based transition-state mimics, we constructed a focused library of 624 macrocyclic compounds. Screening identified several subnanomolar inhibitors with desirable pharmacokinetic and antifungal properties. Lead compound 25 exhibited a K_i of 180 pM, significant selectivity against host proteases, and potent antifungal activity in culture. The streamlined synthetic approach not only yielded drug-like macrocycles with potential in antifungal therapy but also provided insights into structure-activity relationships that can inform broader applications of macrocyclization in drug discovery.

100 项与 Major Aspartyl Peptidase 1 inhibitors(University of Charles) 相关的药物交易

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