Publications by authors named "O CALLAGHAN"
Phenylethylamine and its monomethylated derivatives p-methylphenylethylamine, α-methylphenylethylamine, phenylethylamine itself, N-methylphenylethylamine, o-methylphenylethylamine, and β-methylphenylethylamine, readily cross the blood-brain barrier showing a brain-uptake index (%) ± SD (water considered 100 %), of 108 ± 11, 98 ± 14, 83 ± 6, 78 ± 11, 62 ± 7 and 56 ± 6, respectively (injection of tritiated water and 100 μg standard amine, which was measured by gas-liquid chromatography). Similar brain-uptake index values (determined by double isotope counting) were obtained for phenylethylamine and α-methylphenylethylamine (amphetamine) after the injection of tritiated water and C(14)-labeled amine (either 3 μg or when added 100 μg standard compound), suggesting that they entered the brain via passive diffusion. Accordingly, both amines distributed rather evenly in the various rat brain areas examined: uptake index (%) ± SD (double isotope counting; non-, and diluted labeled amine) for phenylethylamine (89 ± 8 and 78 ± 7, 83 ± 9 and 86 ± 9, 96 ± 6 and 84 ± 7) and for α-methylphenylethylamine (88 ± 11 and 87 ± 9, 93 ± 14 and 87 ± 11, 97 ± 12 and 87 ± 9) for the cerebellum, frontal cortex, and striatum, respectively.
View Article and Find Full Text PDFEighteen male cluster headache (CH) inpatients within a CH series participated in this research. Blood samples were drawn from patients at least 6-hour pain-free after the last acute CH episode and then shortly prior (SP), during, and soon after (SA) a new acute CH attack. Three healthy male, age-comparable drug-free volunteers served as controls; 5 samples were obtained from each of these individual over a 24-hour period.
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- * An aminopyrimidine was found to have high micromolar affinity, which was then improved through structure-based design into a more effective low nanomolar compound.
- * A fragment with phenolic structure was also optimized to achieve subnanomolar affinity for Hsp90, demonstrating a remarkable 1,000,000-fold increase in affinity with minimal modifications, leading to a compound currently in clinical trials for cancer treatment.
Article Synopsis
- Fragment-based lead discovery was used to develop inhibitors for urokinase-type plasminogen activator (uPA), starting with the drug mexiletine (R)-5.
- Through structure-aided design, researchers created enhanced inhibitors that maintained crucial interactions while increasing potency by targeting additional areas of the active site.
- The final optimized compound, designated as 15, emerged as a strong, selective, and orally bioavailable uPA inhibitor.
Article Synopsis
- - Fragment-based lead generation successfully identified a new series of cyclic amidine inhibitors for beta-secretase (BACE-1), starting with initial compounds that showed millimolar activity through NMR screening.
- - Efforts to improve these fragments involved structure-guided techniques using X-ray crystallography and potency testing, resulting in the development of stronger micromolar inhibitors.
- - Further optimization led to the discovery of dihydroisocytosines, achieving submicromolar potency with Compound 29 being the most promising candidate with an IC50 of 80 nM for future research.