RESUMO
Previously disclosed H4 receptor modulators, the triamino substituted pyridines and pyrimidines, contain a free primary amino (-NH2) group. In this Letter we demonstrate that an exocyclic amine (NH2) is not needed to maintain affinity, and also show a significant divergence in the SAR of the pendant diamine component. These des-NH2 azacycles also show a distinct functional spectrum, that appears to be influenced by the diamine component; in the case of the 1,3-amino pyrimidines, the preferred diamine is the amino pyrrolidine instead of the more common piperazines. Finally, we introduce 3,5-diamino pyridazines as novel histamine H4 antagonists.
Assuntos
Piridinas/farmacologia , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Histamínicos/efeitos dos fármacos , Humanos , Piridinas/química , Receptores Histamínicos H4RESUMO
During the course of our efforts toward the discovery of human histamine H4 antagonists from a series of 2-aminiopyrimidines, it was noted that a 6-trifluoromethyl group dramatically reduced affinity of the series toward the histamine H4 receptor. This observation was further investigated by synthesizing a series of ligands that varied in pKa of the pyrimidine derived H4 ligands by over five orders of magnitude and the effect on histamine H4 affinity. This trend was then extended to the discovery of C-linked piperidinyl-2-amino pyridines as histamine H4 receptor antagonists.
Assuntos
Antagonistas dos Receptores Histamínicos/farmacocinética , Piridinas/química , Pirimidinas/química , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Histamínicos/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Ligantes , Estrutura Molecular , Receptores Histamínicos H4RESUMO
Two series of triamino pyrimidines and a series of triamino pyridines have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. Small structural changes in these three hetereoaromatic cores influenced the functional activity of these compounds.
Assuntos
Piridinas/farmacologia , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Aminas/química , Ligação Competitiva , Bioensaio , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Piridinas/síntese química , Piridinas/química , Pirimidinas/síntese química , Pirimidinas/química , Receptores Histamínicos , Receptores Histamínicos H4 , Relação Estrutura-AtividadeRESUMO
This report discloses the development of a series of tricyclic histamine H(4) receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H(4) receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.
Assuntos
Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Antagonistas dos Receptores Histamínicos/química , Camundongos , Receptores Histamínicos , Receptores Histamínicos H4RESUMO
Leukotrienes (LTs) and related species are proinflammatory lipid mediators derived from arachidonic acid (AA) that have pathological roles in autoimmune and inflammatory conditions, cardiovascular diseases, and cancer. 5-Lipoxygenase activating protein (FLAP) plays a critical accessory role in the conversion of AA to LTA4, and its subsequent conversion to LTC4 by LTC4 synthase. Pharmacological inhibition of FLAP results in a loss of LT production by preventing the biosynthesis of both LTB4 and LTC4, making it an attractive target for the treatment of inflammatory diseases in which LTs likely play a role. Small-molecule (SM) drugs often exhibit polypharmacology through various pathways, which may explain the differential therapeutic efficacies of compounds sharing structural similarity. We have profiled a series of SM FLAP modulators for their selectivity across enzymes of AA cascade in human whole blood (HWB), using a recently developed LC/MS (liquid chromatography-mass spectrometry)-based high-throughput lipidomics platform that monitors 122 eicosanoids in multiplex. Highly efficient data acquisition coupled with fast and accurate data analysis allowed facile compound profiling from ex vivo study samples. This platform allowed us to quantitatively map the effects of those SMs on the entire AA cascade, demonstrating its potential to discriminate structurally related compounds.
Assuntos
Proteínas Ativadoras de 5-Lipoxigenase/química , Bibliotecas de Moléculas Pequenas/química , Eicosanoides/química , Glutationa Transferase/química , Humanos , Leucotrienos/química , PolifarmacologiaRESUMO
A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.
Assuntos
Inibidores de Caspase , Hepatopatias/tratamento farmacológico , Ácidos Pentanoicos/síntese química , Adulto , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Disponibilidade Biológica , Caspase 3 , Colestase/tratamento farmacológico , Colestase/patologia , Ensaios Clínicos Fase I como Assunto , Meia-Vida , Hepatite C Crônica/tratamento farmacológico , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Células Jurkat , Fígado/efeitos dos fármacos , Fígado/patologia , Hepatopatias/enzimologia , Hepatopatias/etiologia , Camundongos , Ácidos Pentanoicos/química , Ácidos Pentanoicos/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The first nonpeptidic, noncovalent inhibitors of the cysteine protease cathepsin S (CatS) are described. Electronic database searching using the program DOCK generated a screening set of potential CatS inhibitors from which two lead structures were identified as promising starting points for a drug discovery effort. Lead optimization afforded potent (IC(50) < 50 nM) and selective inhibitors of CatS demonstrating cellular activity and reversibility of enzyme inhibition.
Assuntos
Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Catepsinas/química , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos/métodos , Antígenos de Histocompatibilidade Classe II/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Regiões Constantes de Imunoglobulina/efeitos dos fármacos , Regiões Constantes de Imunoglobulina/metabolismo , Concentração Inibidora 50 , Peptídeos/química , Peptídeos/farmacologia , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
High potency pyrazole-based noncovalent inhibitors of human cathepsin S (CatS) were developed by modification of the benzo-fused 5-membered ring heterocycles found in earlier series of CatS inhibitors. Although substitutions on this heterocyclic framework had a moderate impact on enzymatic potency, dramatic effects on cellular activity were observed. Optimization afforded indole- and benzothiophene-derived analogues that were high affinity CatS inhibitors (IC(50)=20-40 nM) with good cellular potency (IC(50)=30-340 nM).
Assuntos
Catepsinas/antagonistas & inibidores , Catepsinas/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Animais , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Estrutura Molecular , Inibidores de Proteases/química , Pirazóis/síntese química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologiaRESUMO
A novel series of competitive, reversible cathepsin S (CatS) inhibitors was discovered and optimized. The 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety was found to be an effective replacement for the 4-arylpiperazin-1-yl group found in our earlier series of CatS inhibitors. This replacement imparted improved PK properties as well as decreased off-target activity. Optimization of the ketobenzimidazole moiety led to the discovery of the lead compound JNJ 10329670, which represents a novel class of selective, noncovalent, reversible, and orally bioavailable inhibitors of cathepsin S.
Assuntos
Catepsinas/antagonistas & inibidores , Animais , Benzimidazóis/química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Linhagem Celular , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Modelos Químicos , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Various heterocyclic hetero-methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A study of their structure-activity relationship (SAR) related to caspase-1, -3, -6, and -8 is reported. Their efficacy in a cellular model of cell death is also discussed. Potent broad-spectrum caspase inhibitors have been identified.
Assuntos
Inibidores de Caspase , Morte Celular/efeitos dos fármacos , Inibidores de Cisteína Proteinase/farmacologia , Compostos Heterocíclicos/farmacologia , Cetonas/farmacologia , Animais , Ácido Aspártico/química , Células Cultivadas , Compostos Heterocíclicos/síntese química , Cetonas/síntese química , Camundongos , Modelos Biológicos , Naftóis/química , Relação Estrutura-Atividade , Valina/químicaRESUMO
Various aryloxy methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A systematic study of their structure-activity relationship (SAR) related to caspases 1, 3, 6, and 8 is reported. Highly potent irreversible broad-spectrum caspase inhibitors have been identified. Their efficacy in cellular models of cell death and inflammation are also discussed.
Assuntos
Inibidores de Caspase , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Relação Estrutura-AtividadeRESUMO
A new structural class of broad spectrum caspase inhibitors was optimized for its activity against caspases 1, 3, 6, 7, and 8. The most potent compound had low nanomolar broad spectrum activity, in particular, single digit nanomolar inhibitory activity against caspase 8.
Assuntos
Inibidores de Caspase , Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Acilação , Indicadores e Reagentes , Isoenzimas/antagonistas & inibidores , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Relação Estrutura-AtividadeRESUMO
Structural modifications were made to a previously described acyl dipeptide caspase inhibitor, leading to the oxamyl dipeptide series. Subsequent SAR studies directed toward the warhead, P2, and P4 regions of this novel peptidomimetic are described herein.