ABSTRACT
It is well-documented that serotonin (5-HT) exerts its pharmacological effects through a series of 5-HT receptors. The most recently identified member of this family, 5-HT7, was first identified in 1993. Over the course of the last 25 years, this receptor has been the subject of intense investigation, and it has been demonstrated that 5-HT7 plays an important role in a wide range of pharmacological processes. As a result of these findings, modulation of 5-HT7 activity has been the focus of numerous drug discovery and development programs. This review provides an overview of the roles of 5-HT7 in normal physiology and the therapeutic potential of this interesting drug target.
Subject(s)
Drug Discovery/trends , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemistry , Serotonin Receptor Agonists/chemistry , Animals , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Nervous System Diseases/drug therapy , Nervous System Diseases/metabolism , Protein Multimerization/drug effects , Protein Multimerization/physiology , Protein Structure, Secondary , Receptors, Serotonin/metabolism , Serotonin/chemistry , Serotonin/metabolism , Serotonin Antagonists/metabolism , Serotonin Antagonists/therapeutic use , Serotonin Receptor Agonists/metabolism , Serotonin Receptor Agonists/therapeutic useABSTRACT
Inhibition of receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs) has been validated by recently launched small molecules Sutent and Nexavar, both of which display activities against several angiogenesis-related RTKs. EphB4, a receptor tyrosine kinase (RTK) involved in the processes of embryogenesis and angiogenesis, has been shown to be aberrantly up regulated in many cancer types such as breast, lung, bladder and prostate. We propose that inhibition of EphB4 in addition to other validated RTKs would enhance the anti-angiogenic effect and ultimately result in more pronounced anti-cancer efficacy. Herein we report the discovery and SAR of a novel series of imidazo[1,2-a]pyrazine diarylureas that show nanomolar potency for the EphB4 receptor, in addition to potent activity against several other RTKs.
Subject(s)
Angiogenesis Inhibitors/chemistry , Imidazoles/chemistry , Phenylurea Compounds/chemistry , Protein Kinase Inhibitors/chemistry , Pyrazines/chemistry , Receptor, EphB4/antagonists & inhibitors , Urea/analogs & derivatives , Angiogenesis Inhibitors/pharmacology , Cell Line, Tumor , Humans , Imidazoles/pharmacology , Phenylurea Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrazines/pharmacologyABSTRACT
An account is given of the author's several approaches to the synthesis of the parent chromophore of phytochrome (1), a protein-bound linear tetrapyrrole derivative that controls photomorphogenesis in higher plants. These studies culminated in enantioselective syntheses of both 2R- and 2S-phytochromobilin (4), as well as several (13)C-labeled derivatives designed to probe the site of Z,E-isomerization during photoexcitation. When reacted in vitro, synthetic 2R-4 and recombinant-derived phytochrome apoprotein N-C produced a protein-bound chromophore with identical difference spectra to naturally occurring 1.
