Article
Chemistry, Medicinal
Liang Ye, Yifei yang, Chunmei Li, Jianzhao Zhang, Wenyan Wang, Mingxu Ma, Hengwei Xu, Wenjing Zhang, Fangxia Zou, Zhengping Hu, Hongbo Wang, Jingwei Tian
Summary: The study found that pharmacological blockade of neurokinin B (NKB) signaling with an oral NK3R antagonist significantly improved hot flash symptoms, suggesting NK3R as a viable drug target. A series of novel imidazolepiperazine derivatives were designed and synthesized, among which compound 16x showed promising inhibitory activity against NK3R. In vivo studies demonstrated that 16x was orally active, efficacious, and well-tolerated in a specific model, indicating its potential for further development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Biswajit Kundu, Deblina Raychaudhuri, Ayan Mukherjee, Bishnu Prasad Sinha, Dipika Sarkar, Purbita Bandopadhyay, Sourav Pal, Nirmal Das, Debdeep Dey, Kantubhukta Ramarao, Kasireddy Nagireddy, Dipyaman Ganguly, Arindam Talukdar
Summary: The study highlights the importance of C2, C6, and N9 substitutions in the purine scaffold for antagonism to TLR7 and TLR9. A lead compound 29 with promising in vivo antagonism efficacy against mouse TLR9 and therapeutic efficacy in a preclinical murine model of psoriasis is identified as a potential therapeutic candidate in relevant autoimmune contexts.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Veronica Calvo, David Surguladze, An-Hu Li, Matthew D. Surman, Srikanth Malibhatla, Madhavarao Bandaru, Suresh Krishna Jonnalagadda, Ravi Adarasandi, Madhusudhan Velmala, Durga Rama Prasad Singireddi, Mahendar Velpuri, Bhaskar Reddy Nareddy, Visweswara Sastry, Chiranjeevi Mandati, Rambabu Guguloth, Shapi Siddiqui, Basanagoud S. Patil, Elena Chad, Jennifer Wolfley, Jennifer Gasparek, Kirsten Feldman, Matthew Betzenhauser, Brent Wiens, Mary Koszelak-Rosenblum, Guangyu Zhu, Hongwen Du, Alan C. Rigby, Mark J. Mulvihill
Summary: In this study, a series of potent, selective, and orally bioavailable PERK inhibitors were identified, with compound (28) showing robust pharmacokinetics and significant tumor growth inhibition in a renal cell carcinoma xenograft model. This compound warrants further investigation as a tool compound for mechanistic studies.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Zhuang Miao, Yuhan Zhong, Yu Gan, Kequan Fu, Wencheng Liu, Zhihua Cao, Tiantian Zhao, Ziyuan Li, Ao Hai, Yanlai Peng, Zeping Zuo, Tian Zhang, Shilong Hu, Chunxia Chen, Ting Kang, Tianguang Huang, Dong Guo, Bowen Ke
Summary: A new class of dual mu OR agonist/sigma R-1 antagonist has been reported, which exhibits robust analgesic effects with reduced side effects. The optimal compound, 4x, shows potent mu OR agonism activity and good sigma R-1 inhibitory activity, making it a promising lead compound for developing safer opioids.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Bowen Zhang, Chang Liu, Zhenqian Yang, Sai Zhang, Xiaolin Hu, Baohu Li, Mei Mao, Xiao Wang, Zhuoyue Li, Shumin Ma, Siqi Zhang, Chong Qin
Summary: We have developed small molecular PROTAC compounds that can effectively degrade AR-FL and AR-V7 proteins, and showed superior potency compared to the corresponding antagonists in prostate cancer cells. The representative compound BWA-522 achieved high oral bioavailability in both mice and beagle dogs. In a xenograft model study, BWA-522 demonstrated significant tumor growth inhibition, making it a promising AR-NTD PROTAC for treating AR-FL- and AR-V7-dependent tumors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Weilin Chen, Xin Chen, Dongdong Li, Jianrui Zhou, Zhengyu Jiang, Qidong You, Xiaoke Guo
Summary: The WDR5-MLL1 inhibitor compound 63 (DDO-2213) presented potent inhibitory effects and in vivo efficacy, showing potential for treating MLL-rearranged cancers.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Kristina Puls, Aina-Leonor Olive-Marti, Szymon Pach, Birgit Pinter, Filippo Erli, Gerhard Wolber, Mariana Spetea
Summary: In this study, the new opioid ligand Compound A was characterized as a kappa-opioid receptor (KOR) antagonist both in vitro and in vivo. It demonstrated moderate binding affinity to the human KOR and selective binding profile compared to the mu-opioid receptor (MOR) and delta-opioid receptor (DOR). In addition, Compound A effectively reversed the antinociceptive effects of a KOR agonist in mice. Computer simulations revealed the structural determinants responsible for its selective binding to the KOR. This new compound holds promise for the development of potential therapeutics.
Article
Chemistry, Medicinal
Mengna Zhang, Biao Xu, Ning Li, Run Zhang, Qinqin Zhang, Xuerui Shi, Kangtai Xu, Jian Xiao, Dan Chen, Jiandong Niu, Yonghang Shi, Quan Fang
Summary: Stable and orally bioavailable analogues of DN-9 achieving peripherally restricted analgesia with reduced side effects have been developed. Among these analogues, analogue 1 showed improved potency for kappa-opioid and NPFF2 receptors and exhibited powerful, long-lasting antinociceptive effects in mouse models of acute, inflammatory, and neuropathic pain without significant side effects at effective analgesic doses.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Mitja M. Zdouc, Mohammad M. Alanjary, Guadalupe S. Zarazua, Sonia Maffioli, Max Cruesemann, Marnix H. Medema, Stefano Donadio, Margherita Sosio
Summary: Microbial natural products are known for their bioactivity, structural diversity, and ingenious biosynthesis. In this study, two cyclopeptides featuring an unusual Tyr-His biaryl bridging were discovered from the less exploited actinobacterial genus Planomonospora. The genomes of Planomonospora pointed towards a ribosomal synthesis mechanism for the cyclopeptide, involving the smallest coding gene ever reported and a cytochrome P450 monooxygenase likely responsible for biaryl installment.
CELL CHEMICAL BIOLOGY
(2021)
Article
Chemistry, Medicinal
Qian He, Yuanyuan Wei, Xiao Liu, Rongrong Ye, Linghui Kong, Zixiang Li, Shuang Jiang, Linqian Yu, Jingrui Chai, Qiong Xie, Wei Fu, Yujun Wang, Wei Li, Zhuibai Qiu, Jinggen Liu, Liming Shao
Summary: In search for safer selective kappa OR agonists, a series of m-substituted analogs were designed and synthesized resulting in compound 6c (SLL-1206) with single-digit nanomolar activities. Compound 6c showed subtype selectivity by significantly reducing affinity for mu OR and delta OR, leading to improved physicochemical and pharmacokinetic properties compared to SLL-039.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Jing You, Wei Yang, Ronggang Ma, Anjie Xia, Guo Zhang, Zhen Fang, Nihong Guo, Shengyong Yang, Linli Li
Summary: This study reports the discovery of a series of 2-vinyl-10Hphenothiazine derivatives as new class of ferroptosis inhibitors. Compound 7j was identified as a lead compound with reduced hERG inhibition and maintained high ferroptosis inhibitory activity. Further studies showed that 7j acted as an ROS scavenger and could relieve DOX-induced cardiomyopathy.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Fangfang Li, Feng Yue, Wei Zhang, Biao Xu, Yiqing Wang, Xuehong Zhang
Summary: This study developed a novel opioid analgesic, HAGD, which produced equipotent or even greater antinociception compared with morphine in mouse pain models. HAGD also showed reduced side effects compared to morphine, including analgesic tolerance, rewarding effects, and gastrointestinal transit inhibition.
