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










Base de dados
Intervalo de ano de publicação
1.
ACS Med Chem Lett ; 11(4): 550-557, 2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32292563

RESUMO

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field of cancer immunotherapy, as the upregulation of IDO1 in certain cancers has been linked to host immune evasion and poor prognosis for patients. In particular, IDO1 inhibition is of interest as a combination therapy with immune checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, a diamide class of compounds was identified as a promising lead for the inhibition of IDO1. While hit 1 possessed attractive cell-based potency, it suffered from a significant right-shift in a whole blood assay, poor solubility, and poor pharmacokinetic properties. Through a physicochemical property-based approach, including a focus on lowering AlogP98 via the strategic introduction of polar substitution, compound 13 was identified bearing a pyridyl oxetane core. Compound 13 demonstrated improved whole blood potency and solubility, and an improved pharmacokinetic profile resulting in a low predicted human dose.

2.
Bioorg Med Chem Lett ; 21(7): 2034-9, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21334892

RESUMO

The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB(1) antagonist with high predicted human oral bioavailability.


Assuntos
Indóis/farmacocinética , Receptor CB1 de Canabinoide/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Humanos , Indóis/administração & dosagem , Indóis/química , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 20(24): 7327-30, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21074434

RESUMO

Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo.


Assuntos
Amidas/química , Compostos Azabicíclicos/síntese química , Compostos Bicíclicos com Pontes/química , Indóis/síntese química , Piperazinas/química , Receptor CB1 de Canabinoide/agonistas , Animais , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Desenho de Fármacos , Humanos , Indóis/química , Indóis/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Piperazinas/síntese química , Piperazinas/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 20(18): 5449-53, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20719511

RESUMO

The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.


Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Indóis/química , Indóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Animais , Benzimidazóis/metabolismo , Benzimidazóis/farmacocinética , Humanos , Hipotermia/induzido quimicamente , Hipotermia/tratamento farmacológico , Indóis/metabolismo , Indóis/farmacocinética , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Obesidade/tratamento farmacológico , Ratos , Ratos Wistar , Solubilidade , Relação Estrutura-Atividade
6.
Drug News Perspect ; 21(3): 183-8, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18560617

RESUMO

On December 6, 2007, the Society for Medicines Research held a one-day meeting entitled Recent Disclosures of Clinical Drug Candidates. The meeting brought together speakers from around the world representing both the pharmaceutical industry and academia. The meeting provided an overview of some of the latest approaches being taken in a range of therapeutic areas such as oncology, immunology, central nervous system disease, gastroenterology and antiviral research.


Assuntos
Tratamento Farmacológico/tendências , Animais , Indústria Farmacêutica/tendências , Humanos , Preparações Farmacêuticas
8.
Mol Pharmacol ; 68(5): 1484-95, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16113085

RESUMO

We investigated the pharmacology of three novel compounds, Org 27569 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)-ethyl]-amide), Org 27759 (3-ethyl-5-fluoro-1H-indole-2-carboxylic acid [2-94-dimethylamino-phenyl)-ethyl]-amide), and Org 29647 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide, 2-enedioic acid salt), at the cannabinoid CB1 receptor. In equilibrium binding assays, the Org compounds significantly increased the binding of the CB1 receptor agonist [3H]CP 55,940 [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol], indicative of a positively cooperative allosteric effect. The same compounds caused a significant, but incomplete, decrease in the specific binding of the CB1 receptor inverse agonist [3H]SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride], indicative of a limited negative binding cooperativity. Analysis of the data according to an allosteric ternary complex model revealed that the estimated affinity of each Org compound was not significantly different when the radioligand was [3H]CP 55,940 or [3H]SR 141716A. However, the estimated cooperatively factor for the interaction between modulator and radioligand was greater than 1 when determined against [3H]CP 55,940 and less than 1 when determined against [3H]SR 141716A. [3H]CP 55,940 dissociation kinetic studies also validated the allosteric nature of the Org compounds, because they all significantly decreased radioligand dissociation. These data suggest that the Org compounds bind allosterically to the CB1 receptor and elicit a conformational change that increases agonist affinity for the orthosteric binding site. In contrast to the binding assays, however, the Org compounds behaved as insurmountable antagonists of receptor function; in the reporter gene assay, the guanosine 5'-O-(3-[35S]thio)triphosphate binding assay and the mouse vas deferens assay they elicited a significant reduction in the Emax value for CB1 receptor agonists. The data presented clearly demonstrate, for the first time, that the cannabinoid CB1 receptor contains an allosteric binding site that can be recognized by synthetic small molecule ligands.


Assuntos
Receptor CB1 de Canabinoide/efeitos dos fármacos , Regulação Alostérica , Animais , Sítios de Ligação , Cicloexanóis/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Masculino , Camundongos , Piperidinas/metabolismo , Pirazóis/metabolismo , Receptor CB1 de Canabinoide/química , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/fisiologia
9.
Drug News Perspect ; 18(2): 142-8, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15883623

RESUMO

On December 2, 2004, the Society for Medicines Research held the seventh Trends in Medicinal Chemistry one-day meeting. The meeting brought together speakers from Europe representing both academia and industry and provided an overview of some of the latest approaches being taken in a range of therapeutic areas such as oncology, antiinfectives, CNS disease and reproductive medicine.


Assuntos
Pesquisa Biomédica/tendências , Química Farmacêutica/tendências , Tratamento Farmacológico/tendências , Sociedades Científicas , Animais , Congressos como Assunto , Humanos , Reino Unido
11.
Drug News Perspect ; 18(10): 657-62, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16491168

RESUMO

The Society for Medicines Research symposium Challenges Facing Drug Discovery in Vascular Disease was held September 30, 2005, at Organon Research, Newhouse, Scotland. The conference brought together an international panel of speakers representing academia and the pharmaceutical industry to review approaches to the treatment of diseases affecting the vasculature. The focus of the meeting was on atherosclerosis and one of its clinical manifestations, stroke. The meeting reviewed current and emerging therapeutic approaches and improving technologies to monitor risk and disease progression in patients.


Assuntos
Aterosclerose/tratamento farmacológico , Congressos como Assunto , Acidente Vascular Cerebral/tratamento farmacológico , Doenças Vasculares/tratamento farmacológico , Animais , Aterosclerose/etiologia , Humanos , Escócia , Doenças Vasculares/prevenção & controle
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...