bms-694153 has been researched along with Migraine-Disorders* in 4 studies
4 other study(ies) available for bms-694153 and Migraine-Disorders
| Article | Year |
|---|---|
Discovery of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BMS-742413): a potent human CGRP antagonist with superior safety profile for the treatment of migr
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. Topics: Administration, Intranasal; Amides; Animals; Caco-2 Cells; Calcitonin Gene-Related Peptide Receptor Antagonists; Callithrix; Coronary Vessels; Drug Evaluation, Preclinical; Face; Humans; Indazoles; Migraine Disorders; Quinolones; Rabbits; Rats; Receptors, Calcitonin Gene-Related Peptide; Respiratory Mucosa | 2013 |
Calcitonin gene-related peptide (CGRP) receptor antagonists: pyridine as a replacement for a core amide group.
In our continuing efforts to identify CGRP receptor antagonists that can be dosed orally for the treatment of migraine headache, we have investigated a pyridine bioisosteric replacement of a polar amide portion of a previous lead compound, BMS-694153. Pyridine derivatives were discovered and their SAR was studied. Some of them showed excellent binding potency. However, oral bioavailability was low, even for compounds with good Caco-2 cell permeability. Topics: Amides; Caco-2 Cells; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Inhibitory Concentration 50; Migraine Disorders; Molecular Structure; Protein Binding; Pyridines | 2012 |
Carbamates as potent calcitonin gene-related peptide antagonists with improved solution stability.
The calcitonin gene-related peptide (CGRP) receptor has been implicated in the pathogenesis of migraine. A class of urethanamide derivatives has been identified as potent inhibitors of the CGRP receptor. Compound 20 was found to be among the most potent (IC(50)=17pM). It was shown to retain excellent aqueous solubility (>50mg/mL, pH 7) while dramatically improving solution stability as compared to our previously disclosed development candidate, BMS-694153 (1). Topics: Calcitonin Gene-Related Peptide Receptor Antagonists; Carbamates; Drug Stability; Humans; Indazoles; Migraine Disorders; Quinazolinones; Quinolones; Receptors, Calcitonin Gene-Related Peptide | 2009 |
Discovery of (R)-4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide (BMS-694153): a potent antagonist of the human calcitonin gene-related peptid
Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Early chemistry leads suffered from modest potency, significant CYP3A4 inhibition, and poor aqueous solubility. Herein, we describe the optimization of these leads to give 4 (BMS-694153), a molecule with outstanding potency, a favorable predictive toxicology profile, and remarkable aqueous solubility. Compound 4 has good intranasal bioavailability in rabbits and shows dose-dependent activity in validated in vivo and ex vivo migraine models. Topics: Administration, Intranasal; Animals; Biological Availability; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Callithrix; Coronary Vessels; Face; Humans; Indazoles; Migraine Disorders; Quinazolinones; Rabbits; Regional Blood Flow; Vasodilation | 2008 |