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1.
Bioorg Med Chem Lett ; 26(13): 3182-3186, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27210432

RESUMO

Novel isoxazoline amide benzoxaboroles were designed and synthesized to optimize the ectoparasiticide activity of this chemistry series against ticks and fleas. The study identified an orally bioavailable molecule, (S)-N-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)-2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (23), with a favorable pharmacodynamics profile in dogs (Cmax=7.42ng/mL; Tmax=26.0h; terminal half-life t1/2=127h). Compound 23, a development candidate, demonstrated 100% therapeutic effectiveness within 24h of treatment, with residual efficacy of 97% against American dog ticks (Dermacentor variabilis) on day 30 and 98% against cat fleas (Ctenocephalides felis) on day 32 after a single oral dose at 25mg/kg in dogs.


Assuntos
Amidas/farmacologia , Antiparasitários/farmacologia , Compostos de Boro/farmacologia , Ctenocephalides/efeitos dos fármacos , Dermacentor/efeitos dos fármacos , Ectoparasitoses/tratamento farmacológico , Isoxazóis/farmacologia , Administração Oral , Amidas/administração & dosagem , Amidas/química , Animais , Antiparasitários/administração & dosagem , Antiparasitários/química , Compostos de Boro/administração & dosagem , Compostos de Boro/química , Gatos , Cães , Relação Dose-Resposta a Droga , Ectoparasitoses/parasitologia , Isoxazóis/administração & dosagem , Isoxazóis/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 25(23): 5589-93, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26508546

RESUMO

A novel series of isoxazoline benzoxaborole small molecules was designed and synthesized for a structure-activity relationship (SAR) investigation to assess the ectoparasiticide activity against ticks and fleas. The study identified an orally bioavailable molecule, (S)-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (38, AN8030), which was long lasting in dogs (t1/2=22 days). Compound 38 demonstrated 97.6% therapeutic effectiveness within 24 h of treatment, with residual efficacy of 95.3% against American dog ticks (Dermacentor variabilis) on day 30% and 100% against cat fleas (Ctenocephalides felis) on day 32 after a single oral dose at 50 mg/kg in dogs.


Assuntos
Compostos de Boro/química , Doenças do Cão/tratamento farmacológico , Descoberta de Drogas , Ectoparasitoses/tratamento farmacológico , Isoxazóis/síntese química , Administração Oral , Animais , Compostos de Boro/administração & dosagem , Compostos de Boro/farmacologia , Doenças do Cão/parasitologia , Cães , Isoxazóis/administração & dosagem , Isoxazóis/química , Isoxazóis/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Fatores de Tempo
3.
J Med Chem ; 45(12): 2624-43, 2002 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-12036372

RESUMO

A series of analogues of the protein kinase C (PKC) inhibitory natural product balanol which bear modified benzophenone subunits are described. The analogues were designed with the goal of uncovering structure-activity features that could be used in the development of PKC inhibitors with a reduced polar character compared to balanol itself. The results of these studies suggest that most of the benzophenone features found in the natural product are important for obtaining potent PKC inhibitory compounds. However, several modifications were found to lead to selective inhibitors of the related enzyme protein kinase A (PKA), and several specific modifications to the polar structural elements of the benzophenone were found to provide potent PKC inhibitors. In particular, it was found that replacement of the benzophenone carboxylate with bioisosteric equivalents could lead to potent analogues. Further, a tolerance for lipophilic substituents on the terminal benzophenone ring was uncovered. These results are discussed in light of recently available structural information for PKA.


Assuntos
Azepinas/síntese química , Benzofenonas/síntese química , Inibidores Enzimáticos/síntese química , Hidroxibenzoatos/síntese química , Proteína Quinase C/antagonistas & inibidores , Azepinas/química , Benzofenonas/química , Inibidores Enzimáticos/química , Humanos , Hidroxibenzoatos/química , Isoenzimas/antagonistas & inibidores , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 15(10): 2553-7, 2005 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-15863315

RESUMO

Syntheses and SAR studies of 3,3-bisaryloxindole analogues provided potent mineralocorticoid receptor (MR) antagonists that were selective over other steroid nuclear hormone receptors.


Assuntos
Indóis/farmacologia , Antagonistas de Receptores de Mineralocorticoides , Humanos , Ensaio Radioligante
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