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1.
Eur J Med Chem ; 276: 116686, 2024 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-39053192

RESUMEN

With an objective to improve the profiles of the 1st generation non-basic MCHR1 antagonists, a lean design approach of replacing the bicyclic thienopyrimidine core with a monocyclic pyrrol-2-one chemotype was examined in the context of reducing aromatic ring count, while also contemplating enhanced flexibility as a means of decreasing flat character. The new compounds exhibited potent antagonism up to the sub-nanomolar range, thereby implying that the monocyclic ring could effectively serve as an effective bioisostere of the bicyclic system. The prototype compound 2m offered benefits like improved potency, reduced half-life, and enhanced solubility, while also demonstrating >5% reduction in weight gain in rats, thereby providing proof-of-concept for this new class of compounds as anti-obesity agents.


Asunto(s)
Pirroles , Animales , Ratas , Relación Estructura-Actividad , Humanos , Estructura Molecular , Pirroles/farmacología , Pirroles/química , Pirroles/síntesis química , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/química , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Masculino , Ratas Sprague-Dawley , Receptores de Somatostatina
2.
ACS Med Chem Lett ; 15(2): 181-188, 2024 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-38352830

RESUMEN

We have designed and developed novel and selective TLR7 agonists that exhibited potent receptor activity in a cell-based reporter assay. In vitro, these agonists significantly induced secretion of cytokines IL-6, IL-1ß, IL-10, TNFa, IFNa, and IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodynamic studies in mice showed a significant secretion of IFNα and TNFα cytokines. When combined with aPD1 in a CT-26 tumor model, the lead compound showed strong synergistic antitumor activity with complete tumor regression in 8/10 mice dosed using the intravenous route. Structure-activity relationship studies enabled by structure-based designs of TLR7 agonists are disclosed.

3.
J Org Chem ; 88(19): 13553-13567, 2023 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-37708032

RESUMEN

Against the backdrop of the well-known O-sulfonylation of cyclopropyl alcohols with sulfonyl chlorides, we examined the feasibility of conducting regioselective C-sulfonylation. By emulating an umpolung strategy-guided design, we report for the first time the Cu(II)-catalyzed ß-sulfonylation of cyclopropanols by a mechanism that potentially involves an oxidative addition of a sulfonyl radical to a metal homoenolate. Unlike reported methods, this protocol allows a practical synthetic route to γ-keto sulfone building blocks from cyclopropanols by leveraging commercially available aryl- and alkyl-sulfonyl chlorides, common reagents in organic chemistry laboratories. Using operationally simple open-flask conditions, the preparative scope of starting materials was demonstrated using an array of aryl- and alkyl-substituted sulfonyl chlorides and cyclopropanols (43 examples, up to 96% yield).

4.
J Med Chem ; 65(16): 11150-11176, 2022 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-35952307

RESUMEN

Structure-property relationships associated with a series of (carbonyl)oxyalkyl amino acid ester prodrugs of the marketed HIV-1 protease inhibitor atazanavir (1), designed to enhance the systemic drug delivery, were examined. Compared to previously reported prodrugs, optimized candidates delivered significantly enhanced plasma exposure and trough concentration (Cmin at 24 h) of 1 in rats while revealing differentiated PK paradigms based on the kinetics of prodrug activation and drug release. Prodrugs incorporating primary amine-containing amino acid promoieties offered the benefit of rapid bioactivation that translated into low circulating levels of the prodrug while delivering a high Cmax value of 1. Interestingly, the kinetic profile of prodrug cleavage could be tailored for slower activation by structural modification of the amino terminus to either a tertiary amine or a dipeptide motif, which conferred a circulating depot of the prodrug that orchestrated a sustained release of 1 along with substantially reduced Cmax and a further enhanced Cmin.


Asunto(s)
Profármacos , Aminas , Aminoácidos/química , Animales , Sulfato de Atazanavir/farmacología , Sistemas de Liberación de Medicamentos , Profármacos/química , Ratas
5.
J Org Chem ; 86(21): 14356-14370, 2021 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-34554740

RESUMEN

In contrast to the conventional 1,4-addition process, regioselective 1,2-addition of silyl enol ethers to quinones can now be achieved via a palladium(II) enolate pathway that provides access to 4-hydroxy-4-(2-oxo-2-arylethyl)cyclohexa-2,5-dien-1-one derivatives. This quinone alkylation protocol proceeds under mild reaction conditions at ambient temperature under open air and does not require either an external ligand for the palladium or the use of a base. Additionally, the cyclohexadienone products have been exploited as synthetic precursors for the construction of fused heteroaryl systems.


Asunto(s)
Paladio , Silanos , Catálisis , Ligandos , Quinonas
6.
J Med Chem ; 62(7): 3553-3574, 2019 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-30938524

RESUMEN

Phosphate and amino acid prodrugs of the HIV-1 protease inhibitor (PI) atazanavir (1) were prepared and evaluated to address solubility and absorption limitations. While the phosphate prodrug failed to release 1 in rats, the introduction of a methylene spacer facilitated prodrug activation, but parent exposure was lower than that following direct administration of 1. Val amino acid and Val-Val dipeptides imparted low plasma exposure of the parent, although the exposure of the prodrugs was high, reflecting good absorption. Screening of additional amino acids resulted in the identification of an l-Phe ester that offered an improved exposure of 1 and reduced levels of the circulating prodrug. Further molecular editing focusing on the linker design culminated in the discovery of the self-immolative l-Phe-Sar dipeptide derivative 74 that gave four-fold improved AUC and eight-fold higher Ctrough values of 1 compared with oral administration of the drug itself, demonstrating a successful prodrug approach to the oral delivery of 1.


Asunto(s)
Aminoácidos/química , Sulfato de Atazanavir/química , Sulfato de Atazanavir/farmacocinética , Diseño de Fármacos , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacocinética , Fosfatos/química , Profármacos/química , Profármacos/farmacocinética , Administración Oral , Animales , Área Bajo la Curva , Sulfato de Atazanavir/administración & dosificación , Sulfato de Atazanavir/síntesis química , Disponibilidad Biológica , Ésteres , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/síntesis química , Humanos , Profármacos/administración & dosificación , Profármacos/síntesis química
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