33452-18-5Relevant academic research and scientific papers
INHIBITORS OF CYCLIN-DEPENDENT KINASE 7 (CDK7)
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Paragraph 333; 335, (2019/08/08)
The present invention provides, inter alia, compounds having the structures of formulas described herein; pharmaceutically acceptable salts, solvates, hydrates, tautomers, and isotopic forms thereof; and compositions (e.g., pharmaceutical compositions and kits) containing one or more of the foregoing. Also provided are methods of administering and uses involving the compounds and/or pharmaceutical compositions for treating or preventing disease. The disease can be a proliferative disease, such as a cancer (e.g., a blood cancer (e.g., a leukemia or lymphoma), a brain cancer, a breast cancer, melanoma, multiple myeloma, or an ovarian cancer) a benign neoplasm, pathologic angiogenesis, or a fibrotic disease. While no aspect of the invention is limited by the biological events that may transpire, administering a compound or other composition described herein may selectively inhibit the aberrant expression or activity of cyclin-dependent kinase 7 (CDK7) and, thereby, induce cellular apoptosis and/or inhibit the transcription of disease-related genes in the patient (or in a biological sample).
Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT2C Receptor Agonists
Carpenter, Joseph,Wang, Ying,Wu, Gang,Feng, Jianxin,Ye, Xiang-Yang,Morales, Christian L.,Broekema, Matthias,Rossi, Karen A.,Miller, Keith J.,Murphy, Brian J.,Wu, Ginger,Malmstrom, Sarah E.,Azzara, Anthony V.,Sher, Philip M.,Fevig, John M.,Alt, Andrew,Bertekap, Robert L.,Cullen, Mary Jane,Harper, Timothy M.,Foster, Kimberly,Luk, Emily,Xiang, Qian,Grubb, Mary F.,Robl, Jeffrey A.,Wacker, Dean A.
, p. 6166 - 6190 (2017/08/02)
Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.
