Discovery of Isoindoline Amide Derivatives as Potent and Orally Bioavailable ADAMTS-4/5 Inhibitors for the Treatment of Osteoarthritis

被引:6
作者
Zhao, Peng [1 ]
Liu, Dong [1 ]
Song, Chunying [1 ]
Li, Di [1 ]
Zhang, Xinzhu [1 ]
Horecny, Ivana [1 ]
Zhang, Fengqi [1 ]
Yan, Yuna [2 ]
Zhuang, Linghang [1 ]
Li, Jing [1 ]
Liu, Suxing [1 ]
Mao, Yuchang [2 ]
Feng, Jun [2 ]
Liu, Jian [1 ]
Tao, Weikang [2 ]
机构
[1] Etern Biosci Inc, Cranbury, NJ 08512 USA
[2] Shanghai Hengrui Pharmaceut Co Ltd, Shanghai 200245, Peoples R China
关键词
osteoarthritis; ADAMTS-4; ADAMTS-5; inhibitor; isoindoline; amide; CARTILAGE DEGRADATION; AGGRECAN DEGRADATION; RAT MODEL; EXPRESSION; ENZYMES; DOMAIN; PAIN;
D O I
10.1021/acsptsci.2c00023
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Osteoarthritis (OA) treatment is a highly unmet medical need. Development of a disease-modifying OA drug (DMOAD) is challenging with no approved drugs on the market. Inhibition of ADATMS-4/5 is a promising OA therapeutics to target cartilage degradation and potentially can reduce joint pain and restore its normal function. Starting from the reported ADAMTS-5 inhibitor GLPG1972, we applied a scaffold hopping strategy to generate a novel isoindoline amide scaffold. Representative compound 18 showed high potency in ADATMS-4/5 inhibition, as well as good selectivity over a panel of other metalloproteases. In addition, compound 18 exhibited excellent druglike properties and showed better pharmacokinetic (PK) proliles than GLPG1972 cross-species. Compound 18 demonstrated dose-dependent efficacy in two in vivo rat osteoarthritis models.
引用
收藏
页码:458 / 467
页数:10
相关论文
共 50 条
[41]   Discovery of N-(5,6-diarylpyridin-2-yl)amide derivatives as potent and selective A2B adenosine receptor antagonists [J].
Eastwood, Paul ;
Gonzalez, Jacob ;
Paredes, Sergio ;
Nueda, Arsenio ;
Domenech, Teresa ;
Alberti, Joan ;
Vidal, Bernat .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (05) :1697-1700
[42]   Discovery and Optimization of a-Mangostin Derivatives as Novel PDE4 Inhibitors for the Treatment of Vascular Dementia [J].
Liang, Jinhao ;
Huang, Yi-You ;
Zhou, Qian ;
Gao, Yuqi ;
Li, Zhe ;
Wu, Deyan ;
Yu, Si ;
Guo, Lei ;
Chen, Zhen ;
Huang, Ling ;
Liang, Steven H. ;
He, Xixin ;
Wu, Ruibo ;
Luo, Hai-Bin .
JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (06) :3370-3380
[43]   Discovery and biological evaluation of N5-substituted 6,7-dioxo-6,7-dihydropteridine derivatives as potent Bruton's tyrosine kinase inhibitors [J].
Chen, Haiyang ;
Song, Peiran ;
Diao, Yanyan ;
Hao, Yongjia ;
Dou, Dou ;
Wang, Wanqi ;
Fang, Xiaoyu ;
Wang, Yanling ;
Zhao, Zhenjiang ;
Ding, Jian ;
Li, Honglin ;
Xie, Hua ;
Xu, Yufang .
MEDCHEMCOMM, 2018, 9 (04) :697-704
[44]   Discovery of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as potent and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-1 [J].
Muthukaman, Nagarajan ;
Tambe, Macchindra ;
Deshmukh, Sanjay ;
Pisal, Dnyandeo ;
Tondlekar, Shital ;
Shaikh, Mahamadhanif ;
Sarode, Neelam ;
Kattige, Vidya G. ;
Pisat, Monali ;
Sawant, Pooja ;
Honnegowda, Srinivasa ;
Karande, Vikas ;
Kulkarni, Abhay ;
Behera, Dayanidhi ;
Jadhav, Satyawan B. ;
Sangana, Ramchandra R. ;
Gudi, Girish S. ;
Khairatkar-Joshi, Neelima ;
Gharat, Laxmikant A. .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2017, 27 (23) :5131-5138
[45]   Discovery of Novel 5-(Piperazine-1-carbonyl)pyridin-2(1H)-one Derivatives as Orally eIF4A3-Selective Inhibitors [J].
Mizojiri, Ryo ;
Nakata, Daisuke ;
Satoh, Yoshihiko ;
Morishita, Daisuke ;
Shibata, Sachio ;
Iwatani-Yoshihara, Misa ;
Kosugi, Yohei ;
Kosaka, Mai ;
Takeda, Junpei ;
Sasaki, Shigekazu ;
Takami, Kazuaki ;
Fukuda, Koichiro ;
Kamaura, Masahiro ;
Sasaki, Shinobu ;
Arai, Ryosuke ;
Cary, Douglas R. ;
Imaeda, Yasuhiro .
ACS MEDICINAL CHEMISTRY LETTERS, 2017, 8 (10) :1077-1082
[46]   Discovery of Novel Retigabine Derivatives as Potent KCNQ4 and KCNQ5 Channel Agonists with Improved Specificity [J].
Wang, Lei ;
Qiao, Guan-Hua ;
Hu, Hai-Ning ;
Gao, Zhao-Bing ;
Nan, Fa-Jun .
ACS MEDICINAL CHEMISTRY LETTERS, 2019, 10 (01) :27-33
[47]   Pharmacophore-Oriented Discovery of Novel 1,2,3-Benzotriazine-4-one Derivatives as Potent 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors [J].
Yan, Yao-Chao ;
Wu, Wei ;
Huang, Guang-Yi ;
Yang, Wen-Chao ;
Chen, Qiong ;
Qu, Ren-Yu ;
Lin, Hong-Yan ;
Yang, Guang-Fu .
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 2022, 70 (22) :6644-6657
[48]   Discovery of CZS-241: A Potent, Selective, and Orally Available Polo-Like Kinase 4 Inhibitor for the Treatment of Chronic Myeloid Leukemia [J].
Sun, Yin ;
Xue, Yanli ;
Liu, Hongbing ;
Mu, Shuyi ;
Sun, Pengkun ;
Sun, Yu ;
Wang, Lin ;
Wang, Hanxun ;
Wang, Jingkai ;
Wu, Tianxiao ;
Yin, Wenbo ;
Qin, Qiaohua ;
Sun, Yixiang ;
Yang, Huali ;
Zhao, Dongmei ;
Cheng, Maosheng .
JOURNAL OF MEDICINAL CHEMISTRY, 2023, 66 (04) :2396-2421
[49]   Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors [J].
Goto, Taiji ;
Shiina, Akiko ;
Yoshino, Toshiharu ;
Mizukami, Kiyoshi ;
Hirahara, Kazuki ;
Suzuki, Osamu ;
Sogawa, Yoshitaka ;
Takahashi, Tomoko ;
Mikkaichi, Tsuyoshi ;
Nakao, Naoki ;
Takahashi, Mizuki ;
Hasegawa, Masashi ;
Sasaki, Shigeki .
BIOORGANIC & MEDICINAL CHEMISTRY, 2013, 21 (22) :7025-7037
[50]   Design, synthesis, and biological evaluation of novel piperidine-4-carboxamide derivatives as potent CCR5 inhibitors [J].
Hu, Suwen ;
Gu, Quan ;
Wang, Zhilong ;
Weng, Zhiyong ;
Cai, Yunrui ;
Dong, Xiaowu ;
Hu, Yongzhou ;
Liu, Tao ;
Xie, Xin .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2014, 71 :259-266