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Two tarantula peptides inhibit activation of multiple sodium channels.
These peptides are the first high-affinity ligands for tetrodotoxin-resistant peripheral nerve Na( V) channels, but also inhibit other Na(V) channels (IC(50)'s < 100 nM).
Cyclopsychotride A, a biologically active, 31-residue cyclic peptide isolated from Psychotria longipes.
The peptide was found to dose-dependently increase intracellular Ca2+ at concentrations ranging from 3 to 30 microM, and this response was not blocked by a known NT antagonist.
Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of
Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations, leading to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
Structure-Function Relationships in the Neuropeptide S Receptor
The results identify the key residues of NPS involved in NPSR activation and suggest a molecular basis for the functional effects of the N107I mutation and for its putative pathophysiological link with asthma.
Enhancement of α-Helicity in the HIV-1 Inhibitory Peptide DP178 Leads to an Increased Affinity for Human Monoclonal Antibody 2F5 but Does Not Elicit Neutralizing Responses in Vitro
The synthetic peptide DP178, derived from the carboxyl-terminal heptad repeat region of human immunodeficiency virus type 1 GP41 protein is a potent inhibitor of viral-mediated fusion and contains
Progress towards the development of a HIV-1 gp41-directed vaccine.
A rational design approach combining structural characterization with traditional SAR to optimize MAb 2F5 antibody affinities of gp41-based peptide immunogens incorporating variants of both the2F5 epitope and the gp41 ectodomain is described.
Discovery of [(2R,5R)‐5‐{[(5‐Fluoropyridin‐2‐yl)oxy]methyl}‐2‐methylpiperidin‐1‐yl][5‐methyl‐2‐(pyrimidin‐2‐yl)phenyl]methanone (MK‐6096): A Dual Orexin Receptor Antagonist with Potent
The discovery of a series of α‐methylpiperidine carboxamide dual orexin 1 and orexIn 2 receptor (OX1R/OX2R) antagonists (DORAs) is described, inspired by earlier work from this laboratory in understanding preferred conformational properties for potent Orexin receptor binding.
Conformational analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding.
Synthesis and evaluation of a macrocycle that enforces a similar conformation suggest that this geometry mimics the bioactive conformation.
3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency.
Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.
Discovery of a Potent, CNS‐Penetrant Orexin Receptor Antagonist Based on an N,N‐Disubstituted‐1,4‐diazepane Scaffold that Promotes Sleep in Rats
Discovery of a dual (OX1R/OX2R) orexin receptor antagonist featuring a 1,4‐diazepane central constraint that blocks orexIn signaling in vivo is described.