Search

Your search keyword '"Hongwen Zhu"' showing total 4 results
Start Over Author "Hongwen Zhu" Journal journal of medicinal chemistry
4 results on '"Hongwen Zhu"'

1. Discovery of Small-Molecule Degraders of the CDK9-Cyclin T1 Complex for Targeting Transcriptional Addiction in Prostate Cancer

Author

Jiacheng Li, Ting Liu, Yuanli Song, Mingyu Wang, Liping Liu, Hongwen Zhu, Qi Li, Jin Lin, Hualiang Jiang, Kaixian Chen, Kehao Zhao, Mingliang Wang, Hu Zhou, Hua Lin, and Cheng Luo

Subjects
Cell Nucleus, Male, Cyclin T, Cyclins, Drug Discovery, Molecular Medicine, Humans, Prostatic Neoplasms, Cyclin-Dependent Kinase 9, Cyclin-Dependent Kinases
Abstract

Aberrant hyperactivation of cyclins results in carcinogenesis and therapy resistance in cancers. Direct degradation of the specific cyclin or cyclin-dependent kinase (CDK)-cyclin complex by small-molecule degraders remains a great challenge. Here, we applied the first application of hydrophobic tagging to induce degradation of CDK9-cyclin T1 heterodimer, which is required to keep productive transcription of oncogenes in cancers.

Published
2022

2. Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases

Author

Robert E. Davis, Lawrence P. Wennogle, Peng Li, Joseph P. Hendrick, Satoshi Sogabe, Wei Yao, Gyorgy Snell, Hailin Zheng, J. David Beard, Zhao Jun, Gretchen L. Snyder, Lei Zhang, Weston Lane, Koh Ida, Charles J. Heyser, Hongwen Zhu, and Kimberly E. Vanover

Subjects
Male, Models, Molecular, 0301 basic medicine, Drug, Movement disorders, Phosphodiesterase Inhibitors, media_common.quotation_subject, Pharmacology, PDE1, Rats, Sprague-Dawley, Structure-Activity Relationship, 03 medical and health sciences, 0302 clinical medicine, Pyrimidinones, In vivo, Drug Discovery, medicine, Animals, Humans, media_common, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Drug discovery, Mental Disorders, Phosphodiesterase, Neurodegenerative Diseases, Cyclic Nucleotide Phosphodiesterases, Type 1, medicine.disease, Rats, 030104 developmental biology, Schizophrenia, Microsomes, Liver, Molecular Medicine, Cattle, medicine.symptom, Cognition Disorders, 030217 neurology & neurosurgery
Abstract

A diverse set of 3-aminopyrazolo[3,4-d]pyrimidinones was designed and synthesized. The structure-activity relationships of these polycyclic compounds as phosphodiesterase 1 (PDE1) inhibitors were studied along with their physicochemical and pharmacokinetic properties. Systematic optimizations of this novel scaffold culminated in the identification of a clinical candidate, (6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-3-(phenylamino)-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(2H)-one phosphate (ITI-214), which exhibited picomolar inhibitory potency for PDE1, demonstrated excellent selectivity against all other PDE families and showed good efficacy in vivo. Currently, this investigational new drug is in Phase I clinical development and being considered for the treatment of several indications including cognitive deficits associated with schizophrenia and Alzheimer's disease, movement disorders, attention deficit and hyperactivity disorders, and other central nervous system (CNS) and non-CNS disorders.

Published
2016
Full Text
View/download PDF

3. Discovery of a Tetracyclic Quinoxaline Derivative as a Potent and Orally Active Multifunctional Drug Candidate for the Treatment of Neuropsychiatric and Neurological Disorders

Author

Peng Li, John Tomesch, J. David Beard, Wei Yao, Gretchen L. Snyder, Lawrence P. Wennogle, Qiang Zhang, Joseph P. Hendrick, Sharon Mates, Robert E. Davis, Lee Taekyu, Hongwen Zhu, Kimberly E. Vanover, Youyi Peng, and Albert J. Robichaud

Subjects
Male, Biological Availability, Pharmacology, Rats, Sprague-Dawley, Structure-Activity Relationship, In vivo, Quinoxalines, Dopamine receptor D2, Drug Discovery, Lumateperone, Animals, Structure–activity relationship, Receptor, Serotonin, 5-HT2A, Serotonin transporter, Serotonin Plasma Membrane Transport Proteins, Electroshock, Adrenergic Uptake Inhibitors, Behavior, Animal, biology, Receptors, Dopamine D2, Drug discovery, Chemistry, Mental Disorders, Antagonist, Investigational New Drug, Recombinant Proteins, Rats, Quipazine, Schizophrenia, biology.protein, Molecular Medicine, Indicators and Reagents, Serotonin Antagonists, Nervous System Diseases
Abstract

We report the synthesis and structure-activity relationships of a class of tetracyclic butyrophenones that exhibit potent binding affinities to serotonin 5-HT(2A) and dopamine D2 receptors. This work has led to the discovery of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one 4-methylbenzenesulfonate (ITI-007), which is a potent 5-HT(2A) antagonist, postsynaptic D2 antagonist, and inhibitor of serotonin transporter. This multifunctional drug candidate is orally bioavailable and exhibits good antipsychotic efficacy in vivo. Currently, this investigational new drug is under clinical development for the treatment of neuropsychiatric and neurological disorders.

Published
2014
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results