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Drugs Drug Candidates, Volume 3, Issue 2 (June 2024) – 3 articles

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11 pages, 2275 KiB  
Article
Relaxant Activity of 4H-Pyran and 1,6-Dihydropyridine Derivatives on Isolated Rat Trachea
by Samuel Estrada-Soto, Soledad Alemán-Pantitlán, Emmanuel Gaona-Tovar, Fernando Hernández-Borja, Yolanda Alcaraz, Rafael Villalobos-Molina and Miguel A. Vázquez
Drugs Drug Candidates 2024, 3(2), 342-352; https://doi.org/10.3390/ddc3020020 - 11 Apr 2024
Viewed by 387
Abstract
Derivatives of 4H-pyrans and 1,6-dihydropyridines have generated considerable attention due to their interesting biological and therapeutic values. Their pharmacological activities include vasorelaxant, anticarcinogenic, antimicrobial, and antioxidant activities. Thus, the aim of the current work is to determine the relaxant effect of synthesized 4H-pyran [...] Read more.
Derivatives of 4H-pyrans and 1,6-dihydropyridines have generated considerable attention due to their interesting biological and therapeutic values. Their pharmacological activities include vasorelaxant, anticarcinogenic, antimicrobial, and antioxidant activities. Thus, the aim of the current work is to determine the relaxant effect of synthesized 4H-pyran and 1,6-dihydropyridine derivatives with potential anti-asthmatic properties on the smooth muscle airway, with a possible Ca2+-channel blockade as a mechanism of action due to their analogy with 1,4-dihidropyridines. 4H-pyrans and 1,6-dihydropyridines were achieved using multicomponent reactions by microwave and conventional heating. Also, test samples were evaluated ex vivo to determine their relaxant effect on isolated rat tracheal rings pre-contracted with carbachol. All compounds evaluated showed a significant relaxant effect on carbachol-induced contraction in tracheal rat rings. Compounds 4b, 4e, 7a, and 8d were the most potent from the entire series and were also more potent than theophylline, used as a positive control. In conclusion, in the current work some relaxant compounds of the airway smooth muscle with potential to be developed as anti-asthmatic drugs were obtained. Full article
(This article belongs to the Section Medicinal Chemistry and Preliminary Screening)
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14 pages, 2596 KiB  
Review
Sebetralstat: A Rapidly Acting Oral Plasma Kallikrein Inhibitor for the On-Demand Treatment of Hereditary Angioedema
by Edward P. Feener, Rebecca L. Davie, Nivetha Murugesan, Stephen J. Pethen, Sally L. Hampton, Michael D. Smith, Paul K. Audhya and Chris M. Yea
Drugs Drug Candidates 2024, 3(2), 328-341; https://doi.org/10.3390/ddc3020019 - 07 Apr 2024
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Abstract
Sebetralstat is a novel, potent, and selective oral plasma kallikrein inhibitor drug candidate in clinical development for the on-demand treatment of hereditary angioedema (HAE). Upon binding, sebetralstat induces a conformational change in the active site of plasma kallikrein, which contributes to its high [...] Read more.
Sebetralstat is a novel, potent, and selective oral plasma kallikrein inhibitor drug candidate in clinical development for the on-demand treatment of hereditary angioedema (HAE). Upon binding, sebetralstat induces a conformational change in the active site of plasma kallikrein, which contributes to its high potency (Ki 3 nM) and selectivity (>1500 fold) against other serine proteases. Its physiochemical properties promote both rapid dissolution in the stomach and rapid absorption in the upper intestine that contribute to its fast and efficient absorption. A single oral administration of sebetralstat rapidly provides near-complete inhibition of plasma kallikrein and blockade of high-molecular-weight kininogen cleavage as early as 15 min, which drives its clinical efficacy. In a phase 2 clinical trial, sebetralstat significantly reduced the time to beginning of symptom relief (p < 0.0001) with median times of 1.6 h (95% CI: 1.5–3.0) with sebetralstat versus 9.0 h (4.0–17.2) with placebo. KONFIDENT (NCT05259917) is a phase 3 clinical trial assessing the on-demand use of sebetralstat for HAE. If successful, this trial could support the approval of sebetralstat as the first noninvasive, on-demand treatment option to rapidly halt HAE attacks and provide fast symptom relief. Full article
(This article belongs to the Special Issue Drugs of the Kallikrein-Kinin System)
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17 pages, 2357 KiB  
Review
Zilucoplan: A Newly Approved Macrocyclic Peptide for Treatment of Anti-Acetylcholine Receptor Positive Myasthenia Gravis
by Lia Costa and Carla Fernandes
Drugs Drug Candidates 2024, 3(2), 311-327; https://doi.org/10.3390/ddc3020018 - 27 Mar 2024
Viewed by 557
Abstract
Zilucoplan is a synthetic macrocyclic peptide approved by the Food and Drug Administration (FDA), in October 2023, for the treatment of generalized myasthenia gravis. It is considered as an orphan drug that causes the inhibition of terminal complement cascade activation with a dual [...] Read more.
Zilucoplan is a synthetic macrocyclic peptide approved by the Food and Drug Administration (FDA), in October 2023, for the treatment of generalized myasthenia gravis. It is considered as an orphan drug that causes the inhibition of terminal complement cascade activation with a dual mechanism of action preventing the formation of the membrane attack complex (MAC) and the destruction of the neuromuscular junction. This drug has been demonstrated to be able to treat the generalized myasthenia gravis without significant adverse effects, with good efficacy, safety, and tolerability profile. Zilucoplan is not only innovative and promising in the therapeutics of generalized myasthenia gravis, but it could also be beneficial for the treatment of other diseases as well as a model for synthesis of analogues to improve pharmacological profile. Full article
(This article belongs to the Section Marketed Drugs)
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