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1.
Eur J Med Chem ; 243: 114728, 2022 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-36084534

RESUMEN

Currently, there is a significant unmet need for novel analgesics with fewer side effects. In this study, we carried out structural modification of a hit compound previously identified in an artificial-intelligence (AI) virtual screening and discovered the potent analgesic, benzo[b]thiophene-2-carboxamide analog (compound 25) with new structural scaffold. We investigated the signaling pathways of opioid receptors mediated by compound 25, and found this racemic compound activated mu-opioid receptor through the cyclic adenosine monophosphate (cAMP) and ß-arrestin-2-mediated pathways with strong potency and efficacy, and accompanying nociceptin-orphanin FQ opioid peptide and delta-opioid receptors through the cAMP pathway with weak potencies. Compound 25 elicited potent antinociception in thermal-stimulated pain (ED50 value of 127.1 ± 34.65 µg/kg) and inflammatory-induced allodynia models with less gastrointestinal transit inhibition and antinociceptive tolerance than morphine. Overall, this study revealed a novel analgesic with reduced risks of side effects.


Asunto(s)
Analgésicos Opioides , Tiofenos , Humanos , Tiofenos/farmacología , Tiofenos/uso terapéutico , Analgésicos Opioides/efectos adversos , Receptores Opioides mu/agonistas , Receptores Opioides/agonistas , Péptidos Opioides , Morfina/farmacología , Analgésicos/farmacología , Analgésicos/uso terapéutico , Analgésicos/química , Estreñimiento/inducido químicamente , Estreñimiento/tratamiento farmacológico
2.
Eur J Med Chem ; 229: 114043, 2022 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-34929581

RESUMEN

Indoleamine 2,3-dioxygenase-1 (IDO1) is a potential target for the next generation of cancer immunotherapies. We describe the development of two series of IDO1 inhibitors incorporating a N-hydroxy-thiophene-carboximidamide core generated by knowledge-based drug design. Structural modifications to improve the cellular activity and pharmacokinetic (PK) properties of the compounds synthesized, including extension of the side chain of the N-hydroxythiophene-2-carboximidamide core, resulted in compound 27a, a potent IDO1 inhibitor which demonstrated significant (51%) in vivo target inhibition on IDO1 in a human SK-OV-3 ovarian xenograft tumor mouse model. This strategy is expected to be applicable to the discovery of additional IDO1 inhibitors for the treatment of other diseases susceptible to modulation of IDO1.


Asunto(s)
Amidas/química , Diseño de Fármacos , Inhibidores Enzimáticos/química , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Amidas/metabolismo , Animales , Sitios de Unión , Línea Celular Tumoral , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Semivida , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Ratones , Ratones Endogámicos ICR , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Relación Estructura-Actividad , Tiofenos/química , Trasplante Heterólogo
3.
J Med Chem ; 64(17): 12469-12486, 2021 09 09.
Artículo en Inglés | MEDLINE | ID: mdl-34459195

RESUMEN

Designing hybrid molecules with dual functions is one approach to improve the therapeutic efficacy of combination treatment. We have previously conjugated phthalazine and bis(hydroxymethyl)pyrrole pharmacophores to form hybrids bearing antiangiogenesis and DNA interstrand cross-linking activities. To improve the bioavailability, we adopted a benzology approach to design and synthesize a new series of 1,2-bis(hydroxymethyl)benzo[g]pyrrolo[2,1-a]phthalazines. These new hybrids retained the dual functions and could be formulated into vehicles for intravenous and oral administration. Among them, we demonstrated that compound 19a with dimethylamine at the C6 position markedly suppressed the tumor growth of human small cell lung cancer cell line H526, squamous lung cancer cell line H520, and renal cancer cell line 786-O in nude mice, implying that compound 19a is a broad-spectrum anticancer agent. Our results implicated that the conjugation of antiangiogenic and DNA cross-linking is likely to be a helpful approach to improving the efficacy of combination therapy.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Neovascularización Patológica/prevención & control , Ftalazinas/química , Ftalazinas/farmacología , Animales , Línea Celular Tumoral , Supervivencia Celular , Diseño de Fármacos , Humanos , Neoplasias Pulmonares , Ratones , Ratones Desnudos , Neoplasias de Células Escamosas , Carcinoma Pulmonar de Células Pequeñas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
4.
J Med Chem ; 63(4): 1642-1659, 2020 02 27.
Artículo en Inglés | MEDLINE | ID: mdl-31961685

RESUMEN

Indoleamine 2,3-dioxygenase (IDO1) inhibitors are speculated to be useful in cancer immunotherapy, but a phase III clinical trial of the most advanced IDO1 inhibitor, epacadostat, did not meet its primary end point and was abandoned. In previous work, we identified the novel IDO1 inhibitor N-(4-chlorophenyl)-2-((5-phenylthiazolo[2,3-c][1,2,4]triazol-3-yl)thio)acetamide 1 through high-throughput screening (HTS). Herein, we report a structure-activity relationship (SAR) study of this compound, which resulted in the potent IDO1 inhibitor 1-(4-cyanophenyl)-3-(3-(cyclopropylethynyl)imidazo[2,1-b]thiazol-5-yl)thiourea 47 (hIDO IC50 = 16.4 nM). X-ray cocrystal structural analysis revealed that the basis for this high potency is a unique sulfur-aromatic interaction network formed by the thiourea moiety of 47 with F163 and F226. This finding is expected to inspire new approaches toward the discovery of potent IDO1 inhibitors in the future.


Asunto(s)
Inhibidores Enzimáticos/química , Imidazoles/química , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Tiazoles/química , Sitios de Unión , Cristalografía por Rayos X , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Humanos , Imidazoles/síntesis química , Imidazoles/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Estructura Molecular , Unión Proteica , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/metabolismo
5.
Org Lett ; 17(15): 3846-9, 2015 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-26208248

RESUMEN

A novel method for the regio- and stereoselective synthesis of substituted 3-coumaranones from salicylaldehydes and allenes using a rhodium(III) catalyst has been developed. This procedure gives access to new 2-vinyl-substituted 3-coumaranone compounds. The method involves a Rh(III)-catalyzed aldehyde C-H activation and annulation reactions. Moreover, this Rh(III)-catalyzed [4 + 1] annulation reaction has been applied to 2-aminobenzaldehydes to afford 2,2-disubstituted 3-indolinones.


Asunto(s)
Alcadienos/química , Benzaldehídos/química , Cumarinas/síntesis química , Indoles/síntesis química , Rodio/química , Catálisis , Cumarinas/química , Indoles/química , Estructura Molecular , Estereoisomerismo
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