Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup
| Autor: | Neil Flynn, Mary Jane Cullen, Hongwei Zhang, Wei Wang, Susan Glick, Lisa Zhang, Jeffrey A. Robl, Pratik Devasthale, Andres S. Hernandez, Christian Caporuscio, Brian J. Murphy, Suzanne Rooney, Ning Huang, Mary Ann Pelleymounter, Kenneth W. Rohrbach, Kishore Renduchintala, Anthony V. Azzara, Helen E. Godonis, Yi-Xin Li, Radhakrishnan Sridhar, Michael Thomas, Susan Harvey, Paul Stetsko, Mary F. Grubb, Chris Freeden, Fang Moore, Christine Huang, James Devenny, Daniel Longhi, William N. Washburn |
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| Rok vydání: | 2015 |
| Předmět: |
Chemistry
Organic Chemistry Clinical Biochemistry Pharmaceutical Science Pharmacology Biochemistry In vitro Rats Rats Sprague-Dawley Structure-Activity Relationship In vivo Weight Loss Drug Discovery Animals Humans Pyrazoles Molecular Medicine Anti-Obesity Agents Obesity Receptors Somatostatin Molecular Biology Incubation Half-Life Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25:2793-2799 |
| ISSN: | 0960-894X |
| Popis: | Our investigation of the structure–activity and structure–liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate. |
| Databáze: | OpenAIRE |
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