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1.
ACS Med Chem Lett ; 8(12): 1252-1257, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29259743

RESUMO

In an effort to find new therapeutic interventions addressing the unmet medical need of patients with idiopathic pulmonary fibrosis, we initiated a program to identify new autotaxin (ATX) inhibitors. Starting from a recently published compound (PF-8380), we identified several highly potent ATX inhibitors with improved pharmacokinetic and safety profiles. Further optimization efforts resulted in the identification of a single-digit nanomolar lead compound (BI-2545) that shows substantial lowering of LPA in vivo and is therefore considered a valuable tool for further studies.

2.
J Med Chem ; 55(24): 11031-41, 2012 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-23211099

RESUMO

Virtual screening in a huge collection of virtual combinatorial libraries has led to the identification of two new structural classes of GPR119 agonists with submicromolar in vitro potencies. Herein, we describe the virtual screening process involving feature trees fragment space searches followed by a 3D postprocessing step. The in silico findings were then filtered and prioritized, and finally, combinatorial libraries of target molecules were synthesized. Furthermore the so-called "activity-anchor principle" is introduced as an element to increase the chance to generate true hits. An activity anchor is a structural element expected to provide key contributions to a certain biological activity. Application of this technique has led to the discovery of two new GPR119-agonist hit series, one of which was further optimized to progress as a novel lead class.


Assuntos
Bases de Dados Factuais , Modelos Moleculares , Receptores Acoplados a Proteínas G/agonistas , Linhagem Celular , Técnicas de Química Combinatória , Ensaios de Triagem em Larga Escala , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Isoxazóis/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/farmacologia , Receptores Acoplados a Proteínas G/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/síntese química , Ureia/química , Ureia/farmacologia
3.
Bioorg Med Chem Lett ; 21(1): 34-7, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21146986

RESUMO

The discovery of a novel series of 5-HT(2C) agonists based on a tricyclic pyrazolopyrimidine scaffold is described. Compounds with good levels of in vitro potency and moderate to good levels of selectivity with respect to the 5-HT(2A) and 5-HT(2B) receptors were identified. One of the analogues (7 g) was found to be efficacious in a sub-chronic weight loss model. A key limitation of the series of compounds was that they were found to be potent inhibitors of the hERG ion channel. Some compounds, bearing polar side chains were identified which showed a much reduced hERG liability however these compounds were sub-optimal in terms of their in vitro potency or selectivity.


Assuntos
Azepinas/química , Compostos Heterocíclicos com 3 Anéis/química , Indenos/química , Doenças Metabólicas/tratamento farmacológico , Receptor 5-HT2C de Serotonina/química , Agonistas do Receptor 5-HT2 de Serotonina/química , Animais , Compostos Aza/química , Azepinas/farmacocinética , Azepinas/uso terapêutico , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Indenos/farmacocinética , Indenos/uso terapêutico , Masculino , Pirimidinas/química , Ratos , Ratos Wistar , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/química , Receptor 5-HT2B de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Relação Estrutura-Atividade
5.
Arzneimittelforschung ; 54(8): 452-5, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15460212

RESUMO

New stilbene (CAS 56-53-1) derivatives have been synthesized by reductive elimination of desoxybenzoin analogs which were obtained by Fries rearrangement of the corresponding phenolic esters. The chemical structures of the compounds obtained were confirmed by 1H-NMR, IR and elemental analysis. Anti-implantation activity of the compounds was determined by performing experiments with adult male and female Spargue-Dawley rats of proven fertility. A 67% inhibition of implantation was observed separately with compounds 3f and 3i.


Assuntos
Implantação do Embrião/efeitos dos fármacos , Estilbenos/síntese química , Estilbenos/farmacologia , Animais , Feminino , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Masculino , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
6.
Org Lett ; 5(6): 941-4, 2003 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-12633111

RESUMO

[reaction: see text] Bicyclic and tricyclic gamma-butyrolactones with 5,7-, 5,6,5-, 5,6,6-, or 5,7,5-fused ring systems, being found in xanthanolides, eudesmanolides, and guaianolides, were readily synthesized from methyl furan-2-carboxylic acid. Key steps were a copper(I)-catalyzed asymmetric cyclopropanation, Sakurai allylations, intramolecular ene reactions, and ring-closing metathesis reactions.

7.
Chemistry ; 9(1): 260-70, 2003 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-12506382

RESUMO

The development of a new method for the enantioselective synthesis of disubstituted gamma-butyrolactones is reported. Based on this strategy, the total synthesis of three paraconic acids, that is (-)-roccellaric acid, (-)-nephrosteranic acid and (-)-protopraesorediosic acid, and the formal total synthesis of (-)-methylenolactocin and (-)-protolichesterinic acid is described, which are important because of their antibiotic and antitumor properties. Key steps of the synthesis are copper(I)-catalyzed asymmetric cyclopropanations of furans, highly diastereoselective Sakurai allylations, Lewis acid or Lewis base catalyzed retroaldol/lactonization cascades, and ruthenium(II)-catalyzed, intermolecular cross metathesis reactions.

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