87 research outputs found
Phosphoramidate Prodrugs Continue to Deliver, The Journey of Remdesivir (GS-5734) from RSV to SARS-CoV2
No full textRemdesivir (GS-5734) is a monophenol,
2-ethylbutylalanine phosphoramidate
prodrug of a 1′-cyano-4-aza-7,9-dideazaadenosine C-nucleoside
(GS-441524) that is FDA approved for the treatment of hospitalized
patients with COVID-19. The prodrug, initially invented for respiratory
syncytial virus, was later found to have activity toward emerging
RNA viruses, including Ebola and coronaviruses. Remdesivir is among
the first examples of a phosphoramidate prodrug aimed at delivering
a nucleoside monophosphate into lung cells to efficiently generate
the nucleoside triphosphate inhibitor of viral RNA polymerases. With
remdesivir as the central case study, the present work describes the
antiviral potency and in vitro metabolism evidence for lung cell activation
of phosphoramidates, together with their in vivo pharmacokinetics,
lung distribution, and antiviral efficacy toward respiratory viruses.
The lung delivery of nucleoside monophosphate analogs using prodrugs
warrants further investigation toward the development of novel respiratory
antivirals
The Discovery of GS-9131, an Amidate Prodrug of a Novel Nucleoside Phosphonate HIV Reverse Transcriptase Inhibitor
No full textFirst line therapy for treatment-naïve HIV patients typically include the combination of two drugs from the nucleoside or nucleotide class (N(t)RTIs), that target the viral reverse transcriptase (RT), along with either a non-nucleoside RT inhibitor (NNRTI) or HIV protease inhibitor. The N(t)RTIs therefore play an important role as the backbone of choice in HIV regimens, prompting the initiation of a research program aimed at discovering a novel, next generation N(t)RTI. The chapter describes the medicinal strategy that was used to develop a novel nucleoside phosphonate, including structure based design rationales to improve potency, resistance and selectivity. The novel NtRTI GS-9148 (22) that was discovered demonstrated a favorable resistance profile toward many clinically relevant N(t)RTI resistant isolates, and encompassed a rationally designed fluorine group to improve selectivity. To effectively deliver 22 and its active phosphorylated metabolite into lymphoid cells harboring replicating HIV, a unique prodrug strategy was employed. Prodrugs were designed as substrates of lysosomal cathepsin A, a peptidase highly expressed in lymphoid cells, to effectively target in vivo delivery of 22 to the lymphatic system. Ethylalaninyl phosphonamidate prodrug GS-9131 (32) successfully targeted 22 to peripheral blood mononuclear cells upon oral dosing in Beagle dogs (3 mg /kg) and resulted in intracellular active metabolite levels exceeding 9.0 μM, a level 5-fold higher than the HIV RT IC50 of 22. The favorable preclinical profile of 32 led to its nomination as a clinical candidate for the treatment of HIV patients harboring N(t)RTI resistant virus.</jats:p
Anti‐HIV Nucleoside Phosphonate GS‐9148 and Its Prodrug GS‐9131: Scale Up of a 2′‐F Modified Cyclic Nucleoside Phosphonate and Synthesis of Selected Amidate Prodrugs
No full text
ChemInform Abstract: Synthesis and anti‐HIV Activity of Cyclic Pyrimidine Phosphonomethoxy Nucleosides and Their Prodrugs: A Comparison of Phosphonates and Corresponding Nucleosides
No full text2‐(2‐Hydroxy‐3‐alkoxyphenyl)‐1H‐benzimidazole‐5‐carboxamidine Derivatives as Potent and Selective Urokinase‐Type Plasminogen Activator Inhibitors.
No full textAngiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy
No full textMaternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose- and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system
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