Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 60(23): 9807-9820, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-29088532

RESUMO

NMR conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines, or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1', and S2' pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogues, have been found to be brain penetrant BACE-1 inhibitors.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Etilaminas/química , Etilaminas/farmacologia , Peptídeos/química , Peptídeos/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Cristalografia por Raios X , Ciclização , Desenho de Fármacos , Etilaminas/farmacocinética , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Morfolinas/química , Morfolinas/farmacocinética , Morfolinas/farmacologia , Peptídeos/farmacocinética , Inibidores de Proteases/farmacocinética , Relação Estrutura-Atividade
2.
AORN J ; 104(4): 293-306, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27692076

RESUMO

Mitral valve dysfunction can seriously impair patients' lives and may require valve repair or replacement. Surgery can be performed using techniques including sternotomy; right thoracotomy with or without robot assistance; and the totally endoscopic robotic technique, which requires percutaneous techniques, femoral cannulation, and endovascular aortic cross-clamping. The totally endoscopic robotic technique has been facilitated by minimally invasive surgical techniques, the evolution of endoscopic techniques, and the development of surgical robots. These advances have enhanced the view of the surgical field and provide better exposure for the repair or replacement of the mitral valve and subvalvular apparatus. This article describes the totally endoscopic robotic approach to mitral valve surgery as performed at Temple University Hospital, Philadelphia, Pennsylvania.


Assuntos
Doenças das Valvas Cardíacas/cirurgia , Implante de Prótese de Valva Cardíaca/métodos , Valva Mitral/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Humanos , Posicionamento do Paciente , Philadelphia , Cuidados Pré-Operatórios
3.
J Med Chem ; 52(22): 6958-61, 2009 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-19860433

RESUMO

The design, synthesis, and biological characterization of an orally active prodrug (3) of gemcitabine are described. Additionally, the identification of a novel co-crystal solid form of the compound is presented. Valproate amide 3 is orally bioavailable and releases gemcitabine into the systemic circulation after passing through the intestinal mucosa. The compound has entered clinical trials and is being evaluated as a potential new anticancer agent.


Assuntos
Antineoplásicos/química , Desoxicitidina/análogos & derivados , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Neoplasias do Colo/tratamento farmacológico , Cristalização , Cristalografia por Raios X , Citidina/química , Desoxicitidina/administração & dosagem , Desoxicitidina/química , Desoxicitidina/farmacologia , Humanos , Camundongos , Modelos Moleculares , Conformação Molecular , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Solubilidade , Gencitabina
4.
Org Lett ; 11(4): 807-10, 2009 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-19159255

RESUMO

Chiral tertiary alpha-hydroxy esters of known stereochemical configuration were transformed to alpha-azido esters by Mitsunobu reaction with HN3. Optimization of this reaction was shown to proceed at room temperature with high chemical yield using 1,1-(azodicarbonyl)dipiperidine (ADDP) and trimethylphosphine (PMe3). Complete inversion of configuration was observed at the alpha-carbon. Several alpha,alpha-disubstituted amino acids were synthesized in high overall chemical yield and optical purity.


Assuntos
Aminoácidos/química , Aminoácidos/síntese química , Técnicas de Química Combinatória , Catálise , Cromatografia Líquida de Alta Pressão , Ésteres , Estrutura Molecular , Piperidinas/química , Estereoisomerismo
5.
Org Lett ; 10(3): 509-11, 2008 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-18181639

RESUMO

Esters of cyclopropanecarboxylic acid demonstrate a substantial increase in stability under both acid- and base-catalyzed hydrolytic conditions. Comparison of the stability of valacyclovir 13 with the cyclopropane analogue 14 shows that at 40 degrees C and pH 6 the half-life of 14 is >300 h while the value for 13 is 69.7 h. CBS-QB3 calculations on isodesmic reactions for transfer of groups from an alkane to an ester show that a cyclopropyl group provides hyperconjugative stabilization.


Assuntos
Aciclovir/análogos & derivados , Antivirais/química , Ciclopropanos/química , Pró-Fármacos/química , Valina/análogos & derivados , Aciclovir/química , Aciclovir/farmacologia , Antivirais/farmacologia , Ciclopropanos/farmacologia , Ésteres , Hidrólise , Estrutura Molecular , Pró-Fármacos/farmacologia , Valaciclovir , Valina/química , Valina/farmacologia
6.
Bioorg Med Chem Lett ; 16(1): 191-5, 2006 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-16249081

RESUMO

The synthesis of novel macrocyclic peptidomimetic inhibitors of the enzyme BACE1 is described. These macrocycles are derived from a hydroxyethylene core structure. Compound 7 was co-crystallized with BACE1 and the X-ray structure of the complex elucidated at 1.6 Angstrom resolution. This molecule inhibits the production of the Abeta peptide in HEK293 cells overexpressing APP751sw.


Assuntos
Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Desenho de Fármacos , Endopeptidases/química , Endopeptidases/metabolismo , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide , Precursor de Proteína beta-Amiloide/química , Animais , Ácido Aspártico Endopeptidases , Linhagem Celular , Humanos , Cinética , Modelos Químicos , Modelos Moleculares , Conformação Proteica , Estrutura Terciária de Proteína
7.
J Med Chem ; 48(24): 7623-7, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16302802

RESUMO

Conformational analysis in solution of beta-secretase inhibitors 1 and 2 by NMR spectroscopy reveals that the hydroxyethylene isostere, an apparently flexible fragment widely used as a scissile bond replacement in aspartic protease inhibitors, exists in one predominant conformation in solution. This preferred conformation is similar to that adopted by the hydroxyethylene core of 1 in complex with beta-secretase and that adopted by hydroxyethylene cores of related compounds when bound to aspartic proteases, indicating that this structural unit is preorganized in solution.


Assuntos
Dipeptídeos/química , Endopeptidases/química , Inibidores de Proteases/química , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Cristalografia por Raios X , Humanos , Leucina/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Fenilalanina/química , Soluções , Valina/química
8.
J Med Chem ; 48(16): 5104-7, 2005 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-16078829

RESUMO

The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF(1)) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF(1) antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.


Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Imidazóis/síntese química , Piridinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Administração Oral , Hormônio Adrenocorticotrópico/sangue , Animais , Barreira Hematoencefálica/metabolismo , Células CHO , Hormônio Liberador da Corticotropina/farmacologia , Cricetinae , Cricetulus , AMP Cíclico/antagonistas & inibidores , AMP Cíclico/biossíntese , Desenho de Fármacos , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Injeções Intravenosas , Masculino , Piridinas/farmacocinética , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade
9.
J Med Chem ; 48(12): 4100-10, 2005 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-15943483

RESUMO

Two new classes of tricyclic-based corticotropin-releasing factor (CRF(1)) receptor-1 antagonists were designed by constraining known 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine ligands. Pyrrole- and pyrazole-based molecules 19g and 22a, respectively, were discovered that potently bind the recombinant CRF(1) receptor (K(i) = 3.5, 2.9 nM) and inhibit adrenocorticotropic hormone (ACTH) release from rat pituitary cell culture (IC(50) = 14, 6.8 nM). These compounds show good oral bioavailabity (F = 24%, 7.0%) and serum half-lives in rats (t(1/2) = 6.3, 12 h) and penetrate the rat brain ([brain]/[plasma] = 0.27, 0.52) but tend toward large volumes of distribution (V(D) = 38, 44 L kg(-1)) and rapid clearances (CL = 70, 43 mL min(-1) kg(-1)). When given orally, both the pyrazole and the pyrrole leads dose-dependently inhibit stress-induced ACTH release in vivo. ACTH reductions of 84-86% were observed for 30 mg kg(-1) doses.


Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Pirazóis/síntese química , Piridinas/síntese química , Pirróis/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Acenaftenos , Hormônio Adrenocorticotrópico/antagonistas & inibidores , Animais , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Células Cultivadas , AMP Cíclico/biossíntese , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Técnicas In Vitro , Masculino , Camundongos , Hipófise/citologia , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Estresse Psicológico/metabolismo , Relação Estrutura-Atividade
10.
J Med Chem ; 48(5): 1540-9, 2005 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-15743196

RESUMO

Following the discovery of the very high binding affinity of 4-anilinopyrimidines against corticotropin-releasing factor receptor-1 (CRF(1)) (e.g., 1, K(i) = 2 nM), a new series of triazoles bearing different groups has been synthesized and evaluated. The compounds were prepared by cyclizations of N-acyl-S-methylisothioureas with alkylhydrazines or by cyclizations with hydrazine followed by alkylation. While members of this series showed potent binding affinity against CRF(1) receptor, there were important differences between the different regio- (7 and 12) and stereoisomeric aryltriazoles where the R(1) or R(2) side chain in 7 has an asymmetric center. In terms of overall potency, aryltriazole analogues such as 7r bearing an N-(alpha-branched benzyl)-N-propylamino side chain were the most potent, followed by analogues such as 7a, with an N-bis(cyclopropyl)methyl-N-propylamino side chain, and analogues such as 7m, with an N-(alpha-branched aliphatic)-N-propylamino side chain. While the N-propyl group was crucial for high potency, we hypothesized that the terminal methyl mimicked the 5-methyl of pyrazolo[1,5-a]pyrimidines 3 and 4. Correlation of the low-energy conformers of compounds of type 3 and 7 generated by computational analyses was very good. The size and shape of the N-alkyl group dramatically changed the potency of the triazoles, which is in contrast to the SAR seen for bicyclic CRF(1) antagonists. In general, the S-enantiomer was much more potent than the corresponding R-isomer. Furthermore, to a limited extent in the aryltriazole series the substituent on the 5-phenyl ring changed the potency up to 9-fold. (S)-1-Methyl-3-[N-(4-fluorophenylpentyl)-N-propyl]amino-5-(2-methoxy-4-dichlorophenyl)-1H-[1,2,4]triazole [(S)-7r] showed very potent binding affinity (K(i) = 2.7 nM) to CRF(1) receptors with an IC(50) of 49 nM in a cAMP inhibition assay.


Assuntos
Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Triazóis/síntese química , Animais , Barreira Hematoencefálica/metabolismo , Linhagem Celular , AMP Cíclico/biossíntese , Desenho de Fármacos , Fibroblastos/metabolismo , Humanos , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/farmacocinética , Triazóis/farmacologia
11.
J Neurochem ; 91(6): 1249-59, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15584902

RESUMO

Beta-amyloid peptides (Abeta) are produced by a sequential cleavage of amyloid precursor protein (APP) by beta- and gamma-secretases. The lack of Abeta production in beta-APP cleaving enzyme (BACE1)(-/-) mice suggests that BACE1 is the principal beta-secretase in mammalian neurons. Transfection of human APP and BACE1 into neurons derived from wild-type and BACE1(-/-) mice supports cleavage of APP at the canonical beta-secretase site. However, these studies also revealed an alternative BACE1 cleavage site in APP, designated as beta', resulting in Abeta peptides starting at Glu11. The apparent inability of human BACE1 to make this beta'-cleavage in murine APP, and vice versa, led to the hypothesis that this alternative cleavage was species-specific. In contrast, the results from human BACE1 transgenic mice demonstrated that the human BACE1 is able to cleave the endogenous murine APP at the beta'-cleavage site. To address this discrepancy, we designed fluorescent resonance energy transfer peptide substrates containing the beta- and beta'-cleavage sites within human and murine APP to compare: (i) the enzymatic efficiency; (ii) binding kinetics of a BACE1 active site inhibitor LY2039911; and (iii) the pharmacological profiles for human and murine recombinant BACE1. Both BACE1 orthologs were able to cleave APP at the beta- and beta'-sites, although with different efficiencies. Moreover, the inhibitory potency of LY2039911 toward recombinant human and native BACE1 from mouse or guinea pig was indistinguishable. In summary, we have demonstrated, for the first time, that recombinant BACE1 can recognize and cleave APP peptide substrates at the postulated beta'-cleavage site. It does not appear to be a significant species specificity to this cleavage.


Assuntos
Ácido Aspártico Endopeptidases/química , Ácido Aspártico Endopeptidases/genética , Sequência de Aminoácidos , Secretases da Proteína Precursora do Amiloide , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Linhagem Celular , Endopeptidases , Cobaias , Humanos , Cinética , Camundongos , Conformação Molecular , Dados de Sequência Molecular , Proteínas Recombinantes/antagonistas & inibidores , Especificidade da Espécie
12.
Bioorg Med Chem Lett ; 14(24): 6113-6, 2004 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-15546740

RESUMO

To understand the species selectivity in a series of alpha-methyl-alpha-phenoxy carboxylic acid PPARalpha/gamma dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARalpha. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARalpha leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARalpha agonist to a human and mouse dual agonist within the same platform.


Assuntos
Cinamatos/síntese química , Modelos Moleculares , PPAR alfa/agonistas , Animais , Cinamatos/química , Cinamatos/farmacologia , Desenho de Fármacos , Humanos , Ligantes , Camundongos , Estrutura Molecular , Especificidade da Espécie , Relação Estrutura-Atividade
13.
J Med Chem ; 47(19): 4787-98, 2004 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-15341493

RESUMO

We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF(1) receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26 h exhibited good binding affinity at the human CRF(1) receptor with a K(i) value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF(1) receptor (IC(50) = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells (IC(50) = 20 nM). 26 h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26 h was orally bioavailable and able to penetrate into the brain. 26 h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF(1) receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26 h was developed into a clinical compound and exhibited efficacy in patients with major depression.


Assuntos
Desenho de Fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Hormônio Adrenocorticotrópico/metabolismo , Animais , Hormônio Liberador da Corticotropina/farmacologia , AMP Cíclico/metabolismo , Concentração Inibidora 50 , Masculino , Camundongos , Estrutura Molecular , Pirimidinas/administração & dosagem , Pirimidinas/síntese química , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 14(15): 3869-73, 2004 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-15225687

RESUMO

A series of benzoylpyrimidines derived from the anilinepyrimidine CRF(1) antagonists were synthesized. Several synthetic routes were developed to explore the SAR of this series of compounds. Compounds such as 8d (K(i) = 15 nM) exhibited high binding affinities at the human CRF(1) receptor.


Assuntos
Benzoatos/síntese química , Benzoatos/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Benzoatos/química , Clonagem Molecular , Humanos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Pirimidinas/química , Relação Estrutura-Atividade , Termodinâmica
15.
Bioorg Med Chem Lett ; 14(15): 3943-7, 2004 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-15225703

RESUMO

A series of 3-(2-pyridyl)pyrazolo[1,5-a]pyrimidines was designed and synthesized as antagonists for the corticotrophin-releasing factor-1 (CRF(1)) receptor. Several compounds such as 20c (K(i)=10 nM) exhibited good binding affinities at the CRF(1) receptor. In addition, 20c had adequate solubility in water.


Assuntos
Pirazóis/síntese química , Pirimidinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Desenho de Fármacos , Cinética , Modelos Moleculares , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade
16.
Bioorg Med Chem Lett ; 14(14): 3669-73, 2004 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-15203140

RESUMO

In our efforts to identify potent CRF(1) antagonists with proper physicochemical properties, a series of 3-phenylpyrazolo[1,5-a]pyrimidines bearing polar groups, such as amino, hydroxyl, methoxy, sulfoxide, were designed and synthesized. Several positions of the core structure were identified, where a polar group was tolerated with slight reduction in receptor binding. NBI 30545 (18n) was found to have good binding affinity and potent antagonistic activity at the human CRF(1) receptor. Moreover, this compound had proper lipophilicity (log D = 2.78) and good solubility in water (>10mg/mL), and exhibited good plasma and brain exposure when given orally.


Assuntos
Desenho de Fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Hormônio Adrenocorticotrópico/metabolismo , Animais , Ligação Competitiva , Encéfalo/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , AMP Cíclico/metabolismo , Plasma/metabolismo , Pirazóis/síntese química , Pirimidinas/síntese química , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Solubilidade , Relação Estrutura-Atividade , Água/química
17.
J Med Chem ; 47(10): 2422-5, 2004 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-15115385

RESUMO

The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.


Assuntos
Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Fenilpropionatos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Tiofenos/síntese química , Fatores de Transcrição/agonistas , Animais , Ligação Competitiva , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Ensaio Radioligante , Ratos , Ratos Zucker , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologia
18.
Bioorg Med Chem Lett ; 14(9): 2083-6, 2004 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-15080983

RESUMO

A series of 2-dialkylamino-4-phenylpyrimidines (7) was designed and synthesized as CRF(1) antagonists. SAR studies of this series resulted in the discovery of potent and selective antagonists 7b and 7n bearing a 4-(2,4,6-trisubstituted-phenyl) ring and a bulky 2-(N-bis(cyclopropane)methyl-N-propyl)amino group.


Assuntos
Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Desenho de Fármacos , Pirimidinas/química , Ratos , Relação Estrutura-Atividade
19.
Bioorg Med Chem Lett ; 13(24): 4335-9, 2003 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-14643321

RESUMO

Utilizing structure-based techniques and solid-phase synthesis, statine-based tetrapeptide BACE inhibitors were designed and synthesized using a heptapeptide BACE transition-state mimetic, 1, as the starting point. Structure-activity relationship studies at the P(3), P(2), and P(2)' positions as well as the N-terminal capping group on scaffold 5 led to the discovery of potent inhibitors 27, 32, and 34 (IC(50) <100 nM). In addition, computational analysis and the X-ray structure of BACE-inhibitor 38 are discussed.


Assuntos
Aminoácidos/farmacologia , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Doença de Alzheimer/enzimologia , Sequência de Aminoácidos , Aminoácidos/química , Secretases da Proteína Precursora do Amiloide , Desenho de Fármacos , Endopeptidases , Inibidores Enzimáticos/química , Humanos , Cinética , Modelos Moleculares , Relação Estrutura-Atividade
20.
Bioorg Med Chem Lett ; 13(19): 3367-70, 2003 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-12951127

RESUMO

3-Phenylpyrazolo[4,3-b]pyridines were synthesized via a cyclization of 4-amino-3-phenylpyrazoles 11-13 with ethyl acetoacetate. These compounds were found to be potent CRF(1) antagonists. The 2-alkylpyrazolo[4,3-b]pyridines were more polar but less active than the corresponding 1-alkyl-isomers.


Assuntos
Pirazóis/síntese química , Piridinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Humanos , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...