Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to be a global threat due to its ability to evolve and generate new subvariants, leading to new waves of infection. Additionally, other coronaviruses like Middle East respiratory syndrome coronavirus (MERS-CoV, formerly known as hCoV-EMC), which first emerged in 2012, persist and continue to present a threat of severe illness to humans. The continued identification of novel coronaviruses, coupled with the potential for genetic recombination between different strains, raises the possibility of new coronavirus clades of global concern emerging.
View Article and Find Full Text PDFAs SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor.
View Article and Find Full Text PDFAmorphous solid dispersions feature prominently in the approach to mitigate low bioavailability of poorly water-soluble small molecules, particularly in the early development space focusing on toxicity evaluations and clinical studies in normal healthy volunteers, where high exposures are needed to establish safety margins. Spray drying has been the go-to processing route for a number of reasons, including ubiquitous availability of equipment, the ability to accommodate small scale deliveries, and established processes for delivering single phase amorphous material. Active pharmaceutical ingredients (APIs) with low glass transition temperatures (T) can pose challenges to this approach.
View Article and Find Full Text PDFDrug resistance to first-line antimalarials-including artemisinin-is increasing, resulting in a critical need for the discovery of new agents with novel mechanisms of action. In collaboration with the Walter and Eliza Hall Institute and with funding from the Wellcome Trust, a phenotypic screen of Merck's aspartyl protease inhibitor library identified a series of plasmepsin X (PMX) hits that were more potent than chloroquine. Inspired by a PMX homology model, efforts to optimize the potency resulted in the discovery of leads that, in addition to potently inhibiting PMX, also inhibit another essential aspartic protease, plasmepsin IX (PMIX).
View Article and Find Full Text PDFAntimicrob Agents Chemother
September 2022
Tricyclic pyrrolopyrimidines (TPPs) are a new class of antibacterials inhibiting the ATPase of DNA gyrase. TPP8, a representative of this class, is active against Mycobacterium abscessus . Spontaneous TPP8 resistance mutations mapped to the ATPase domain of M.
View Article and Find Full Text PDFNasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective α2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries.
View Article and Find Full Text PDFA novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.
View Article and Find Full Text PDFBackground: Blood vessels of the nasal mucosa are richly innervated by sympathetic nerves and neural mechanism is of great interest in upper respiratory tract disorders. This study was designed to determine the role of α2-adrenoceptors and, more specifically, α2C-adrenoceptors, on neurogenic sympathetic vasoconstrictor responses in pig nasal mucosa, and to define the pharmacologic profile of a novel selective α2C-adrenoreceptor agonist.
Methods: Electrical field stimulation (EFS) was applied to nasal mucosa strips placed in an organ bath and attached to force displacement transducers for continuous recording of isometric tension.
We define the pharmacological and pharmacokinetic profiles of a novel α(2C)-adrenoceptor agonist, compound A [N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1,4-benzoxazin-6-yl]-N-ethyl-N'-methylurea]. This compound has high affinity (K(i)) for the human α(2C)-adrenoceptor (K(i) = 12 nM), and 190- to 260-fold selectivity over the α(2A)- and α(2B)-adrenoceptor subtypes. In cell-based functional assays, compound A produced good agonist (EC(50) = 166 nM) and efficacy (E(max) = 64%) responses at the α(2C)-adrenoceptor, much lower potency and efficacy at the α(2A)-adrenoceptor (EC(50) = 1525 nM; E(max) = 8%) and α(2B)-adrenoceptor (EC(50) = 5814 nM; E(max) = 21%) subtypes, and low or no affinity and functional activity at the α(1A)-, α(1B)-, and α(1D)-adrenoceptor subtypes.
View Article and Find Full Text PDFBackground: Nasal congestion is the most troublesome symptom associated with a variety of upper airway diseases, including allergic rhinitis and the common cold. A better understanding of the mechanisms that regulate nasal cavity caliber may engender the development of novel treatment strategies. It is well accepted that alpha-adrenergic (both alpha(1) and alpha(2)) mechanisms play a fundamental role in the control and maintenance of basal nasal patency.
View Article and Find Full Text PDFStructural features of the substituted 4-piperidinyl urea analogs 1, responsible for the H3 antagonist activity, have been identified. Structure-activity relationship of the H3 receptor affinity, hERG ion channel inhibitory activity and their separation is described. Preliminary pharmacokinetic evaluation of the compounds of the series is addressed.
View Article and Find Full Text PDFThe histamine H(3) receptor is involved in the central and peripheral regulation of levels of histamine and other neurotransmitters (e.g., acetylcholine, noradrenaline, dopamine, serotonin and GABA), which sets it up as a target in the treatment of various CNS (e.
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