Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Bioorg Med Chem Lett ; 29(16): 2265-2269, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31257087

RESUMO

An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.

2.
Medchemcomm ; 8(4): 725-729, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108791

RESUMO

Recently, our research group reported the identification of prodrug amino-alcohol 2 as a potent and efficacious S1P1 receptor modulator. This molecule is differentiated preclinically over the marketed drug fingolimod (Gilenya 1), whose active phosphate metabolite is an S1P1 full agonist, in terms of pulmonary and cardiovascular safety. S1P1 partial agonist 2, however, has a long half-life in rodents and was projected to have a long half-life in humans. The purpose of this communication is to disclose highly potent partial agonists of S1P1 with shorter half-lives relative to the clinical compound 2. PK/PD relationships as well as their preclinical pulmonary and cardiovascular safety assessment are discussed.

3.
J Med Chem ; 53(9): 3814-30, 2010 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-20405922

RESUMO

Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.


Assuntos
Hidantoínas/farmacocinética , Fatores Imunológicos/química , Antígeno-1 Associado à Função Linfocitária/efeitos dos fármacos , Ácidos Nicotínicos/farmacocinética , Humanos , Hidantoínas/farmacologia , Antígeno-1 Associado à Função Linfocitária/química , Antígeno-1 Associado à Função Linfocitária/imunologia , Ácidos Nicotínicos/toxicidade , Relação Estrutura-Atividade
4.
5.
Bioorg Med Chem Lett ; 17(7): 1908-11, 2007 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-17291752

RESUMO

A new class of lymphocyte function-associated antigen-1 (LFA-1) antagonists is described. Elaboration of the 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold resulted in the synthesis of potent inhibitors of the LFA-1/ICAM-1 interaction. Along with the in vitro activity, we present the X-ray crystal structure of the complex of compound 9b, in a novel binding mode to the I-domain of LFA-1.


Assuntos
Química Farmacêutica/métodos , Antígeno-1 Associado à Função Linfocitária/química , Pirróis/química , Cristalografia por Raios X , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Estereoisomerismo , Temperatura Ambiente , Raios X
7.
Bioorg Med Chem Lett ; 13(7): 1345-8, 2003 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-12657279

RESUMO

Screening of our in-house compound collection led to the discovery of 5-bromo-6-amino-2-isoquinoline 1 as a weak inhibitor of IMPDH. Subsequent optimization of 1 afforded a series of novel 2-isoquinolinoaminooxazole-based inhibitors, represented by 17, with single-digit nanomolar potency against the enzyme.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Oxazóis/síntese química , Oxazóis/farmacologia , Avaliação Pré-Clínica de Medicamentos , Escherichia coli/enzimologia , Humanos , NAD/metabolismo , Relação Estrutura-Atividade
8.
Eur J Pharmacol ; 409(3): 301-12, 2000 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-11108825

RESUMO

L-771,688 (SNAP 6383, methyl(4S)-4-(3, 4-difluorophenyl)-6-[(methyloxy)methyl]-2-oxo-3-[(¿3-[4-(2-pyridin yl)-1-piperidinyl]propyl¿amino)carbonyl]-1,2,3, 4-tetrahydro-5-pyrimidine carboxylate) had high affinity (Ki less than or = 1 nM) for [3H]prazosin binding to cloned human, rat and dog alpha1A-adrenoceptors and high selectivity (>500-fold) over alpha1B and alpha1D-adrenoceptors. [3H]Prazosin / (+/-)-beta-[125I]-4-hydroxy-phenyl)-ethyl-aminomethylteralone ([125I]HEAT) binding studies in human and animal tissues known to contain alpha1A and non-alpha1A-adrenoceptors further demonstrated the potency and alpha1A-subtype selectivity of L-771,688. [3H]L-771,688 binding studies at the cloned human alpha1A-adrenoceptors and in rat tissues indicated that specific [3H]L-771,688 binding was saturable and of high affinity (Kd=43-90 pM) and represented binding to the pharmacologically relevant alpha1A-adrenoceptors. L-771,688 antagonized norepinephrine-induced inositol-phosphate responses in cloned human alpha1A-adrenoceptors, as well as phenylephrine or A-61603 (N-[5-4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7, 8-terahydro-naphthlen-1-yl] methanesulfonamide hydrobromide) induced contraction in isolated rat, dog and human prostate, human and monkey bladder neck and rat caudal artery with apparent Kb values of 0.02-0.28 nM. In contrast, the contraction of rat aorta induced by norepinephrine was resistant to L-771,688. These data indicate that L-771,688 is a highly selective alpha1A-adrenoceptor antagonist.


Assuntos
Antagonistas Adrenérgicos alfa/metabolismo , Prazosina/metabolismo , Próstata/metabolismo , Pirimidinonas/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1 , Agonistas alfa-Adrenérgicos/metabolismo , Animais , Cães , Humanos , Imidazóis/metabolismo , Masculino , Fenilefrina/metabolismo , Prazosina/análogos & derivados , Ratos , Tetra-Hidronaftalenos/metabolismo , Bexiga Urinária/metabolismo
9.
J Med Chem ; 42(23): 4764-77, 1999 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-10579840

RESUMO

Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K(i) = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (K(b)(DBP)/K(b)(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntese química , Pirimidinonas/síntese química , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/metabolismo , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Ligação Competitiva , Pressão Sanguínea/efeitos dos fármacos , Cães , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro , Masculino , Próstata/metabolismo , Pirimidinonas/química , Pirimidinonas/metabolismo , Pirimidinonas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/metabolismo , Estereoisomerismo , Uretra/efeitos dos fármacos , Uretra/fisiologia
10.
J Med Chem ; 42(23): 4778-93, 1999 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-10579841

RESUMO

We have previously described compound 1a as a high-affinity subtype selective alpha(1a) antagonist. In vitro and in vivo evaluation of compound 1a showed its major metabolite to be a mu-opioid agonist, 4-methoxycarbonyl-4-phenylpiperidine (3). Several dihydropyrimidinone analogues were synthesized with the goal of either minimizing the formation of 3 by modification of the linker or finding alternative piperidine moieties which when cleaved as a consequence of metabolism would not give rise to mu-opioid activity. Modification of the linker gave several compounds with good alpha(1a) binding affinity (K(i) = < 1 nM) and selectivity (>300-fold over alpha(1b) and alpha(1d)). In vitro analysis in the microsomal assay revealed these modifications did not significantly affect N-dealkylation and the formation of the piperidine 3. The second approach, however, yielded several piperidine replacements for 3, which did not show significant mu-opioid activity. Several of these compounds maintained good affinity at the alpha(1a) adrenoceptor and selectivity over alpha(1b) and alpha(1d). For example, the piperidine fragments of (+)-73 and (+)-83, viz. 4-cyano-4-phenylpiperidine and 4-methyl-4-phenylpiperidine, were essentially inactive at the mu-opioid receptor (IC(50) > 30 microM vs 3 microM for 3). Compounds (+)-73 and (+)-83 were subjected to detailed in vitro and in vivo characterization. Both these compounds, in addition to their excellent selectivity (>880-fold) over alpha(1b) and alpha(1d), also showed good selectivity over several other recombinant human G-protein coupled receptors. Compounds (+)-73 and (+)-83 showed good functional potency in isolated human prostate tissues, with K(b)s comparable to their in vitro alpha(1a) binding data. In addition, compound (+)-73 also exhibited good uroselectivity (DBP K(b)/IUP K(b) > 20-fold) in the in vivo experiments in dogs, similar to 1a.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntese química , Piperidinas/síntese química , Pirimidinonas/síntese química , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/metabolismo , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Cães , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos , Proteínas de Ligação ao GTP/metabolismo , Meia-Vida , Humanos , Técnicas In Vitro , Masculino , Microssomos/metabolismo , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacologia , Próstata/metabolismo , Pirimidinonas/química , Pirimidinonas/metabolismo , Pirimidinonas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Opioides mu/agonistas , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Uretra/efeitos dos fármacos , Uretra/fisiologia
11.
Eur J Pharmacol ; 269(2): 219-24, 1994 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-7851497

RESUMO

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. The synaptic action of GABA is terminated by rapid uptake into presynaptic terminals and surrounding glial cells. Molecular cloning has revealed the existence of four distinct GABA transporters termed GAT-1, GAT-2, GAT-3, and BGT-1. Pharmacological inhibition of transport provides a mechanism for increasing GABA-ergic transmission, which may be useful in the treatment of various neuropsychiatric disorders. Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. These data suggest that the anticonvulsant activity of these compounds is mediated via inhibition of uptake by GAT-1.


Assuntos
Anticonvulsivantes/farmacologia , Proteínas de Transporte/efeitos dos fármacos , Antagonistas GABAérgicos/farmacologia , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso/efeitos dos fármacos , Ácidos Nicotínicos/farmacologia , Ácidos Nipecóticos/farmacologia , Transportadores de Ânions Orgânicos , Oximas/farmacologia , Piridinas/farmacologia , Animais , Anticonvulsivantes/química , Proteínas de Transporte/biossíntese , Linhagem Celular , Clonagem Molecular , Antagonistas GABAérgicos/química , Proteínas da Membrana Plasmática de Transporte de GABA , Humanos , Proteínas de Membrana/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Ácidos Nicotínicos/química , Ácidos Nipecóticos/química , Oximas/química , Piridinas/química , Ratos , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/efeitos dos fármacos , Relação Estrutura-Atividade , Tiagabina , Transfecção
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA