RESUMO
P2X3 receptor is an ATP-gated ion channel, mainly localized on peripheral sensory neurons. Currently, several clinical trials are being conducted with P2X3 receptor antagonists for the treatment of chronic pain or cough. To identify a P2X3 lead compound, we reexamined the HTS evaluation compounds and selected dioxotriazine derivatives from which we identified a hit compound. As a result of the hit-to-lead SAR, we obtained lead compound 1 which had a moderate inhibitory effect on P2X3 receptors (IC50, 128 nM). Further improvement of the potency and PK profiles of this lead compound finally led to the selected compound 74 (P2X3 IC50, 16.1 nM; P2X2/3 IC50, 2931 nM), which demonstrated a strong analgesic effect against allodynia on oral administration in the rat partial sciatic nerve ligation model of neuropathic pain (ED50, 3.1 mg/kg).
Assuntos
Neuralgia/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X3/metabolismo , Triazinas/farmacologia , Administração Oral , Animais , Relação Dose-Resposta a Droga , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Neuralgia/metabolismo , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/química , Ratos , Relação Estrutura-Atividade , Triazinas/administração & dosagem , Triazinas/químicaRESUMO
In previous work, we discovered a lead compound and conducted initial SAR studies on a novel series of dioxotriazines to identify the compound as one of the P2X3 receptor antagonists. This compound showed high P2X3 receptor selectivity and a strong analgesic effect. Although not selected for clinical development, the compound was evaluated from various aspects as a tool compound. In the course of the following study, the molecular structures of the dioxotriazines were modified based on pharmacokinetic/pharmacodynamic (PK/PD) analyses. As a result of these SAR studies, Sivopixant (S-600918) was identified as a clinical candidate with potent and selective antagonistic activity (P2X3 IC50, 4.2 nM; P2X2/3 IC50, 1100 nM) and a strong analgesic effect in the rat partial sciatic nerve ligation model (Seltzer model) of allodynia (ED50, 0.4 mg/kg).
Assuntos
Compostos de Anilina/farmacologia , Descoberta de Drogas , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/farmacologia , Receptores Purinérgicos P2X3/metabolismo , Triazinas/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/químicaRESUMO
The P2X3 receptor is an attractive target for the treatment of pain and chronic coughing, and thus P2X3 antagonists have been developed as new therapeutic drugs. We previously reported selective P2X3 receptor antagonists by derivatization of hit compound 1. As a result, we identified hit compound 3, the structure of which was similar to hit compound 1. On the basis of SAR studies of hit compound 1, we modified hit compound 3 and compound 42 was identified as having analgesic efficacy by oral administration.
Assuntos
Antagonistas do Receptor Purinérgico P2X/química , Antagonistas do Receptor Purinérgico P2X/farmacologia , Pirazolonas/química , Pirazolonas/farmacologia , Receptores Purinérgicos P2X3/metabolismo , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular , Pirróis/química , Pirróis/farmacologia , Receptores Purinérgicos P2X3/química , Relação Estrutura-AtividadeRESUMO
Some P2X3 receptor antagonists have been developed as new therapeutic drugs for pain. We discovered a novel chemotype of P2X3 receptor antagonists with a pyrrolinone skeleton. Because of SAR studies to improve bioavailability of lead compound 2, compound (R)-24 was identified, which showed an analgesic effect against neuropathic pain by oral administration. We constructed a human P2X3 homology model as a template for the zebrafish P2X4 receptor, which agreed with SAR studies of pyrrolinone derivatives.
Assuntos
Antagonistas do Receptor Purinérgico P2X/farmacologia , Pirróis/farmacologia , Receptores Purinérgicos P2X3/efeitos dos fármacos , Administração Oral , Disponibilidade Biológica , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Concentração Inibidora 50 , Neuralgia/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Paclitaxel (Taxol), one of the most potent anticancer drugs, is a microtubule-stabilizing compound that inhibits microtubule depolymerization within the cell. The structure of paclitaxel is composed of two key elements, a taxane ring and an N-benzoylphenylisoserine side chain at C-13. A number of natural and artificial compounds with taxane skeletons have been isolated, but almost none of their bioactivities have been evaluated. In this study, we focused on compounds having a taxane skeleton structure and examined their effects on tubulin dynamics. Although none of these compounds had an N-benzoylphenylisoserine side chain, three were found to promote tubulin assembly. On the other hand, one compound inhibited tubluin assembly in a way similar to nocodazole. These compounds exhibited novel structure-activity relationships of taxane compounds.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Microtúbulos/efeitos dos fármacos , Taxoides/química , Taxoides/farmacologia , Animais , Antineoplásicos , Humanos , Microtúbulos/metabolismo , Estrutura Molecular , Nocodazol , Paclitaxel , Polimerização , Relação Estrutura-Atividade , Tubulina (Proteína)RESUMO
The putative taxol biosynthesis metabolites, taxa-4(20),11(12)-diene-5α, 13α -diol (7), taxa-4(20),11(12)-diene-5α, 9α, 13α-triol (9), and taxa-4(20),11(12)-diene-5α, 10ß, 13α-triol (10), have been prepared by Barton deoxygenation of the C-9 and C10-hydroxyl groups of protected derivatives of taxusin, a major taxoid metabolite isolated from Yew heart wood. The synthetic protocol devised, is amenable for the preparation of isotopically labeled congeners that will be useful to probe further intermediate steps in the biosynthesis of taxol.
RESUMO
Taxa-4(20),11(12)-diene-5α-acetate 5 and Taxa-4(20), 11(12)-diene-5α-acetate, 10ß-ol 6, have been identified as early stage intermediates involved in the biosynthesis of Taxol® (paclitaxel). Tritium-labeled 5 and 6 were successfully prepared by Barton deoxygenation using tri-n-butyltintritiide of the C-14-hydroxyl group of a taxoid obtained from Japanese Yew.
RESUMO
Administering Taxus suspension cells with labeled 5alpha-hydroxytaxadiene and 5alpha,10beta-dihydroxytaxadiene, and the corresponding 5alpha-acetate esters, demonstrated that acetylation at C5 of the monool precursor promotes the formation of 14beta-hydroxy taxoids, such as taxuyunnanine C, at the expense of 13alpha-hydroxy taxoids, including Taxol and its congeners, but that the major bifurcation in taxoid biosynthesis, toward 13alpha- or 14beta-hydroxy taxoids, occurs after 10beta-hydroxylation of the taxane core.
Assuntos
Taxoides/metabolismo , Taxus/metabolismo , Células Cultivadas , Taxus/citologiaRESUMO
Taxa-4(20),11(12)-dien-5 alpha-acetoxy-10 beta-ol 6 has been identified as an early stage intermediate involved in the biosynthesis of taxol (Paclitaxel). This compound has been efficiently prepared by Barton deoxygenation of the C-2- and C-14-hydroxyl groups on a derivative semisynthetically prepared from taxa-4(20),11(12)-dien-2 alpha,5 alpha,10 beta-triacetoxy-14 beta-(2-methyl)butyrate (7), a major taxoid metabolite isolated from Japanese yew heart wood. The synthetic methodology is amenable for the preparation of isotopically labeled congeners that will be useful to probe further intermediate steps in the biosynthesis of taxol.
Assuntos
Antineoplásicos Fitogênicos/biossíntese , Paclitaxel/análogos & derivados , Paclitaxel/biossíntese , Taxoides , Catálise , Estrutura Molecular , Plantas MedicinaisRESUMO
Three novel 4-deacetoxy-1,7-dideoxy azetidine paclitaxel analogues were synthesized through a convenient route that employed hydroboration-amination and intramolecular S(N)2-type substitution reaction from a natural taxoid taxinine. All analogues have been tested for cytotoxicity against three human tumor cell lines. None of them showed remarkable cytotoxicity compared to paclitaxel against tested tumor cell lines.