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MK-8825: A potent and selective CGRP receptor antagonist with good oral activity in rats
- Source :
- Bioorganic & Medicinal Chemistry Letters. 22:3941-3945
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
Abstract
- Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.
- Subjects :
- medicine.medical_specialty
Pyridines
Migraine Disorders
Clinical Biochemistry
Administration, Oral
Biological Availability
Pharmaceutical Science
Calcitonin gene-related peptide
Pharmacology
Biochemistry
Mice
chemistry.chemical_compound
Dogs
Species Specificity
Calcitonin Gene-Related Peptide Receptor Antagonists
In vivo
Internal medicine
Drug Discovery
medicine
Animals
Humans
Potency
Spiro Compounds
Receptor
Molecular Biology
Analgesics
Chemistry
Organic Chemistry
Antagonist
Macaca mulatta
Rats
Blockade
Disease Models, Animal
Endocrinology
Pharmacodynamics
Molecular Medicine
Acetamide
Receptors, Calcitonin Gene-Related Peptide
Subjects
Details
- ISSN :
- 0960894X
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Accession number :
- edsair.doi.dedup.....e62e622cb95d0ea053c8a538444e4e67
- Full Text :
- https://doi.org/10.1016/j.bmcl.2012.04.105