ABSTRACT
An oxidation product (5) formed during the synthesis of BIBN-4096BS (1) was found to be a potent CGRP antagonist (IC50=0.11nM). While 5 was found to be ten-fold less potent than 1, another analog 8 with lower molecular weight containing the oxidized fragment demonstrated twenty-fold higher activity than its parent 7. Alternative conditions which preclude the formation of the oxidation product are described. The activities of 1, 5, 7 and 8 in functional cAMP assay are also discussed.
Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Piperazines/chemistry , Quinazolines/chemistry , Biological Assay , Inhibitory Concentration 50 , Molecular Structure , Oxidation-Reduction , Piperazines/chemical synthesis , Piperazines/pharmacology , Quinazolines/chemical synthesis , Quinazolines/pharmacologyABSTRACT
Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be efficacious as abortive migraine therapeutics with the absence of cardiovascular liabilities that are associated with triptans. Herein, we report the discovery of a highly potent CGRP receptor antagonist, BMS-742413, with the potential to provide rapid onset of action through intranasal delivery. The compound displays excellent aqueous solubility, oxidative stability, and toxicological profile. BMS-742413 has good intranasal bioavailability in the rabbit and shows a robust, dose-dependent inhibition of CGRP-induced increases in marmoset facial blood flow.
Subject(s)
Amides/chemistry , Calcitonin Gene-Related Peptide Receptor Antagonists , Indazoles/chemistry , Quinolones/chemistry , Administration, Intranasal , Amides/pharmacology , Amides/therapeutic use , Animals , Caco-2 Cells , Callithrix , Coronary Vessels/drug effects , Drug Evaluation, Preclinical , Face/blood supply , Humans , Indazoles/pharmacology , Indazoles/therapeutic use , Migraine Disorders/drug therapy , Quinolones/pharmacology , Quinolones/therapeutic use , Rabbits , Rats , Receptors, Calcitonin Gene-Related Peptide/metabolism , Respiratory Mucosa/drug effects , Respiratory Mucosa/pathologyABSTRACT
We report the synthesis of rigid spirocyclic systems as conformationally constrained variants of the Ala-Phe-NH(2) dipeptide amide C-terminus of the calcitonin gene-related peptide (CGRP). CGRP receptor antagonists containing these moieties displayed potent affinity, functional antagonism and excellent oxidative stability. Structure-activity relationship studies demonstrated the relative importance of hydrogen bond donor/acceptor functionalities and the preferred orientation of an aromatic ring. Antagonists showed potent and full reversal of CGRP-induced dilation of ex vivo human intracranial arteries.
Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Spiro Compounds/chemistry , Drug Design , Hydrogen Bonding , Molecular Structure , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
A class of bisarylimidazole derivatives are identified as potent inhibitors of the enzyme fatty acid amide hydrolase (FAAH). Compound 17 (IC(50)=2 nM) dose-dependently (0.1-10mg/kg, iv) potentiates the effects of exogenous anandamide (1 mg/kg, iv) in a rat thermal escape test (Hargreaves test), and shows robust antinociceptive activity in animal models of persistent (formalin test) and neuropathic (Chung model) pain. Compound 17 (20 mg/kg, iv) demonstrates activity in the formalin test that is comparable to morphine (3mg/kg, iv), and is dose-dependently inhibited by the CB1 antagonist SR141716A. In the Chung model, compound 17 shows antineuropathic effects similar to high-dose (100 mg/kg) gabapentin. FAAH inhibition shows potential utility for the clinical treatment of persistent and neuropathic pain.
