Publications by authors named "Paul Blaney"
Class B G-protein-coupled receptors (GPCRs) remain an underexploited target for drug development. The calcitonin receptor (CTR) family is particularly challenging, as its receptors are heteromers comprising two distinct components: the calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of three accessory proteins known as receptor activity-modifying proteins (RAMPs). CLR/RAMP1 forms a CGRP receptor, CLR/RAMP2 forms an adrenomedullin-1 (AM) receptor, and CLR/RAMP3 forms an adrenomedullin-2 (AM) receptor.
View Article and Find Full Text PDFThe hormone adrenomedullin has both physiological and pathological roles in biology. As a potent vasodilator, adrenomedullin is critically important in the regulation of blood pressure, but it also has several roles in disease, of which its actions in cancer are becoming recognized to have clinical importance. Reduced circulating adrenomedullin causes increased blood pressure but also reduces tumor progression, so drugs blocking all effects of adrenomedullin would be unacceptable clinically.
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- - A new inhibitor of the PI3Kδ enzyme is introduced, showing over 200 times more selectivity for other PI3K isoforms and additional kinases.
- - The selectivity is explained using structure-activity relationships and detailed crystal structures of the inhibitor bound to a specific mutant form of PI3Kγ.
- - Pharmacokinetic studies in rats and mice indicate that this inhibitor could be a valuable tool for in vivo research.
Article Synopsis
- PI3Kδ is a lipid kinase found mostly in leukocytes and plays a crucial role in B cell signaling, making it a target for treating diseases like rheumatoid arthritis.
- Researchers discovered new, effective PI3Kδ inhibitors and developed a structural understanding that supports their ability to selectively inhibit different PI3K isoforms (α, β, γ).
- The study highlighted a key element in their design that relates to CYP3A4 time-dependent inhibition, and various strategies were suggested to monitor and reduce this inhibitor issue, utilizing structure-based design for further improvements.
Article Synopsis
- - The addition of a 4-fluorophenylpyrazole group to a previous glucocorticoid receptor antagonist significantly improved its effectiveness in function.
- - The structure-activity relationship (SAR) showed that while small groups (like methyl) had good GR binding, larger groups (like benzyl or aminoalkyl) boosted functional activity even more.
- - New GR antagonists were found with binding and effectiveness similar to mifepristone, showing very strong selectivity for GR over other steroid receptors, and analogues demonstrated over 50% oral bioavailability in dogs.
The 2-azadecalin ring system was evaluated as a scaffold for the preparation of glucocorticoid receptor (GR) antagonists. High affinity, selective GR antagonists were discovered based on a hypothetical binding mode related to the steroidal GR antagonist RU-43044. 2-Benzenesulfonyl substituted 8a-benzyl-hexahydro-2H-isoquinolin-6-ones exemplified by (R)-37 had low nanomolar affinity for GR with moderate functional activity (200 nM) in a reporter gene assay.
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