Potent and Orally Bioavailable Non-Peptide Antagonists at the Human Bradykinin B1 Receptor Based on a 2-Alkylamino-5-sulfamoylbenzamide Core

• Published in: Journal of medicinal chemistry Vol. 47; no. 19; pp. 4642 - 4644
• Main Authors: Ritchie, Timothy J, Dziadulewicz, Edward K, Culshaw, Andrew J, Müller, Werner, Burgess, Gillian M, Bloomfield, Graham C, Drake, Gillian S, Dunstan, Andrew R, Beattie, David, Hughes, Glyn A, Ganju, Pam, McIntyre, Peter, Bevan, Stuart J, Davis, Clare, Yaqoob, Mohammed
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 09.09.2004
• Subjects: Biological and medical sciences; Medical sciences; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Sulfonamide; Oral administration; Non peptide compound; Bioavailability; B1 bradykinin receptor; Morpholine derivatives; Biological activity; Animal; Piperidine derivatives; Carboxamide; Antagonist; Piperazine derivatives; Pharmacokinetics; Chemical synthesis; Aromatic amine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049747g

The bradykinin B1 receptor is rapidly induced after inflammation or tissue trauma and appears to play an important role in the maintenance of hyperalgesia in inflammatory conditions. Here, we describe the optimization process to identify novel, potent non-peptide human B1 receptor antagonists based on a 2-alkylamino-5-sulfamoylbenzamide core. Optimized derivatives are selective, functional B1 antagonists with low nanomolar affinity and exhibit oral bioavailability in animals.