RESUMO
The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperidine scaffold are described herein. The resulting compound 38 exhibit low nanomolar plasma renin IC(50), had a clean CYP 3A4 profile and displayed micromolar affinity for the hERG channel. Furthermore, it was found to be efficacious in the double transgenic rat hypertension model and show good to moderate oral bioavailability in two animal species.
Assuntos
Anti-Hipertensivos/química , Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Piperidinas/química , Piperidinas/uso terapêutico , Renina/antagonistas & inibidores , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Disponibilidade Biológica , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Cães , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
The discovery and SAR of a novel series of spirocyclic renin inhibitors are described herein. It was found that by restricting the northern aromatic plate to the bioactive conformation through spirocyclization, increase in renin potency and decrease in hERG affinity could both be realized. When early members of this series were found to be potent time-dependent CYP3A4 inhibitors, two distinct strategies to address this liability were explored and this effort culminated in the identification of compound 31 as an optimized renin inhibitor.
Assuntos
Anti-Hipertensivos/química , Piperidinas/química , Inibidores de Proteases/química , Renina/antagonistas & inibidores , Compostos de Espiro/química , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/uso terapêutico , Sítios de Ligação , Domínio Catalítico , Simulação por Computador , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Cães , Desenho de Fármacos , Humanos , Hipertensão/tratamento farmacológico , Macaca mulatta , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , Ratos , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
The incorporation of a carboxylic acid within in a series of 3-amido-4-aryl substituted piperidines (represented by general structure 32) led to the discovery of potent, zwitterionic, renin inhibitors with improved off-target profiles (CYP3A4 time-dependent inhibition and hERG affinity) relative to analogous non-zwitterionic inhibitors of the past (i.e., 3). Strategies to address the oral absorption of these zwitterions are also discussed within.
Assuntos
Inibidores de Proteases/síntese química , Renina/antagonistas & inibidores , Administração Oral , Animais , Domínio Catalítico , Simulação por Computador , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacocinética , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Ratos , Ratos Sprague-Dawley , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/efeitos dos fármacos , Ciclopropanos/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Memória de Longo Prazo/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Animais , Ciclopropanos/química , Ciclopropanos/uso terapêutico , Cães , Feminino , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/uso terapêutico , Humanos , Macaca mulatta , Masculino , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound 26b, a highly potent (IC50=0.6 nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Animais , Asma/tratamento farmacológico , Humanos , Concentração Inibidora 50 , Masculino , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacocinética , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
The discovery and SAR of a series of potent renin inhibitors possessing a novel biaryl scaffold are described herein. Molecular modeling revealed that the cyclopropylamide spacer present in 1 can be replaced by a simple, substituted aromatic ring such as a toluene in 2. The resulting compounds exhibit subnanomolar renin IC(50) and good oral bioavailability in rats.
Assuntos
Bibenzilas/química , Inibidores Enzimáticos/química , Renina/antagonistas & inibidores , Administração Oral , Amidas/química , Animais , Bibenzilas/síntese química , Bibenzilas/farmacocinética , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Ratos , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact on the treatment of several degenerative diseases. Here we report the synthesis of reversible inhibitors via a solid-support palladium-catalyzed amination of 3-bromopyrazinones and the discovery of a pan-caspase reversible inhibitor.
Assuntos
Inibidores de Caspase , Paládio/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Aminação , Catálise , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Humanos , Indicadores e Reagentes , Espectrometria de Massas , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
Type 4 phosphodiesterase (PDE4) inhibitors are emerging as new treatments for a number of disorders including asthma and chronic obstructive pulmonary disease. Here we report the biochemical characterization on the second generation inhibitor (+)-1 (L-, IC50=0.4 nM) and its enantiomer (-)-1 (L-, IC50=43 nM) and their cocrystal structures with PDE4D at 2.0 A resolution. Despite the 107-fold affinity difference, both enantiomers interact with the same sets of residues in the rigid active site. The weaker (-)-1 adopts an unfavorable conformation to preserve the pivotal interactions between the Mg-bound waters and the N-oxide of pyridine. These structures support a model in which inhibitors are anchored by the invariant glutamine at one end and the metal-pocket residues at another end. This model provides explanations for most of the observed structure-activity relationship and the metal ion dependency of the catechol-ether based inhibitors and should facilitate their further design.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/química , Óxidos N-Cíclicos/química , Modelos Moleculares , Piridinas/química , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Domínio Catalítico , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Inibidores Enzimáticos/química , Estrutura Molecular , Ligação Proteica , EstereoisomerismoRESUMO
Caspase 3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact in the treatment of several degenerative diseases. The P1 aspartic acid residue is a required element of recognition for this enzyme that was maintained constant along with the adjacent natural valine as the P2 group. The thiobenzylmethylketone warhead on the aspartate was conveniently handled through solid-phase synthesis allowing modification in the P3 region that eventually led to simpler derivatives with increased potency against caspase 3. The key to such an effect is the introduction of hydroxyl group alpha to the P3 carbonyl.
Assuntos
Inibidores de Caspase , Dipeptídeos/síntese química , Cetonas/síntese química , Ácido Aspártico , Caspase 3 , Técnicas de Química Combinatória , Dipeptídeos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Cetonas/farmacologia , Proteínas Recombinantes , Relação Estrutura-Atividade , ValinaRESUMO
A series of potent and selective inhibitors of the inducible microsomal PGE2 synthase (mPGES-1) has been developed based on the indole FLAP inhibitor MK-886. Compounds 23 and 30 inhibit mPGES-1 with potencies in the low nanomolar range and with selectivities of at least 100-fold compared to their inhibition of mPGES-2, thromboxane synthase and binding affinity to FLAP. They also block the production of PGE2 in cell based assays but with a decreased potency and more limited selectivity compared to the enzyme assays.
Assuntos
Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/farmacologia , Indóis/síntese química , Indóis/farmacologia , Oxirredutases Intramoleculares/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/química , Humanos , Indóis/química , Microssomos/enzimologia , Prostaglandina-E Sintases , Relação Estrutura-AtividadeRESUMO
Caspases are cysteine proteases that specifically cleave Asp-Xxx bonds. They are key agents in inflammation and apoptosis and are attractive targets for therapy against inflammation, neurodegeneration, ischemia, and cancer. Many caspase structures are known, but most involve either peptide or protein inhibitors, unattractive candidates for drug development. We present seven crystal structures of inhibited caspase-3 that illustrate several approaches to reducing the peptidyl characteristics of the inhibitors while maintaining their potency and selectivity. The inhibitors reduce the peptidyl nature of inhibitors while preserving binding potency by (1). exploiting a hydrophobic binding site C-terminal to the cleavage site, (2). replacing the negatively charged aspartyl residue at P4 with neutral groups, and (3). using a peptidomimetic 5,6,7-tricyclic system or a pyrazinone at P2-P3. In addition, we have found that two nicotinic acid aldehydes induce a significant conformational change in the S2 and S3 subsites of caspase-3, revealing an unexpected binding mode. These results advance the search for caspase-directed drugs by revealing how unacceptable molecular features can be removed without loss of potency.
Assuntos
Caspases/química , Inibidores Enzimáticos/química , Peptídeos/química , Caspase 3 , Inibidores de Caspase , Cristalografia por Raios X , Compostos Heterocíclicos com 3 Anéis/química , Ligantes , Modelos Moleculares , Mimetismo Molecular , Estrutura Molecular , Niacina/análogos & derivados , Niacina/química , Oligopeptídeos/química , Conformação Proteica , Pirazinas/química , Relação Estrutura-AtividadeRESUMO
A robust method for the solid phase synthesis of a series of selective caspase-3 peptide inhibitors is described. The inhibitors can be obtained after cleavage from the solid support without further purification.
Assuntos
Inibidores de Caspase , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Caspase 3 , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Combinatória , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50RESUMO
The discovery of a series of potent, selective and reversible dipeptidyl caspase-3 inhibitors are reported. The iterative discovery process of using combinatorial chemistry, parallel synthesis, moleculare modelling and structural biology will be discussed.