Topic
Bicyclic molecule
About: Bicyclic molecule is a research topic. Over the lifetime, 29587 publications have been published within this topic receiving 451252 citations. The topic is also known as: bicyclic molecule.
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TL;DR: Results suggest that analogues from this series of 3-pyridylpyrazolo[1,5-a]pyrimidines were potent CRF(1) receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles.
Abstract: We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25−30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF1 receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26h exhibited good binding affinity at the human CRF1 receptor with a Ki value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF1 receptor (IC50 = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells (IC50 = 20 nM). 26h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studie...
126 citations
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126 citations
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126 citations
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TL;DR: The Zr-promoted bicyclization of 1,6-and 1,7-dienes can stereoselectively produce trans-zirconabicyclo[3.3.0] octanes and cis-Zircon-conabicycleclo [4.3] nonanes, respectively; these compounds can be readily converted into protonolysis, halogenolysis and carbonylation products as discussed by the authors.
126 citations