RESUMO
The inhibition of aldosterone synthase (CYP11B2) may be an effective treatment of hypertension and heart failure, among other ailments. Previously reported benzimidazole CYP11B2 inhibitors led the way for bioisosteric imidazopyridines that are both potent and selective over CYP11B1.
Assuntos
Citocromo P-450 CYP11B2/antagonistas & inibidores , Imidazóis/farmacologia , Piridinas/farmacologia , Animais , Cricetulus , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacocinética , Macaca mulatta , Masculino , Microssomos Hepáticos/metabolismo , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Ratos Wistar , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Based on the theoretical understanding of the in vivo lysosomotropism, by adjusting the pk(a) of basic nitrogen containing cathepsin S inhibitors, a set of compounds with pk(a) 6-8 were identified to have excellent cell based Lip10 activity, yet avoiding undesired sequestration in spleen.
Assuntos
Catepsinas/antagonistas & inibidores , Nitrogênio/química , Inibidores de Proteases/química , Piridinas/química , Animais , Catepsinas/metabolismo , Camundongos , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
Using computer aided modelling studies, a new extended P2/S2 interaction was identified. This extended region can accommodate a variety of functional groups, such as aryls and basic amines. It was discovered that the N3 nitrogen of the pyrimidine-2-carbonitrile is critical for its cathepsin cysteine protease inhibition. N1 nitrogen also contributes to the inhibitory activity, but to a very limited degree. An 'in situ double activation' mechanism was proposed to explain these results.
Assuntos
Catepsinas/antagonistas & inibidores , Nitrilas/química , Inibidores de Proteases/química , Pirimidinas/química , Sítios de Ligação , Catepsinas/metabolismo , Simulação por Computador , Humanos , Modelos Moleculares , Nitrilas/síntese química , Nitrilas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologiaRESUMO
The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.
Assuntos
Compostos de Anilina/síntese química , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Amidas/síntese química , Amidas/farmacologia , Compostos de Anilina/farmacologia , Animais , Inibidores de Cisteína Proteinase/farmacologia , Flúor , Humanos , Cetonas , Relação Estrutura-AtividadeRESUMO
Starting from previously disclosed equally potent cathepsin K and S inhibitor 4-propyl-6-(3-trifluoromethylphenyl)pyrimidine-2-carbonitrile 1, a novel 2-phenyl-9H-purine-6-carbonitrile scaffold was identified to provide potent and selective cathepsin S inhibitors.
Assuntos
Catepsinas/antagonistas & inibidores , Nitrilas/química , Inibidores de Proteases/química , Purinas/química , Domínio Catalítico , Catepsina K/antagonistas & inibidores , Catepsina K/metabolismo , Catepsinas/metabolismo , Linhagem Celular , Simulação por Computador , Humanos , Nitrilas/síntese química , Nitrilas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Purinas/síntese química , Purinas/farmacologia , Pirimidinas/químicaRESUMO
PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC50: 80 ± 16 nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases.
Assuntos
Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Sondas Moleculares/farmacologia , Cristalografia por Raios X , Metilação de DNA/efeitos dos fármacos , Inibidores Enzimáticos/química , Células HEK293 , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/ultraestrutura , Histonas/metabolismo , Humanos , Concentração Inibidora 50 , Simulação de Dinâmica Molecular , Sondas Moleculares/química , Domínios Proteicos , S-Adenosilmetionina/metabolismoRESUMO
Herein, we describe the development of a functionally selective liver X receptor ß (LXRß) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-ß peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/líquido cefalorraquidiano , Benzamidas/química , Benzamidas/farmacologia , Receptores Nucleares Órfãos/agonistas , Piperidinas/química , Piperidinas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cães , Células Hep G2 , Humanos , Lipídeos/análise , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado , Locomoção/efeitos dos fármacos , Macaca mulatta , Células Madin Darby de Rim Canino , Camundongos , Camundongos TransgênicosRESUMO
We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
RESUMO
A series of mono- and per-6-substituted cyclodextrin derivatives were synthesized as synthetic receptors (or host molecules) of rocuronium bromide, the most widely used neuromuscular blocker in anaesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramolecular mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compounds, e.g., compound 14 (Org 25969), is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramolecular mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compounds.
Assuntos
Androstanóis/química , Ciclodextrinas/síntese química , Fármacos Neuromusculares não Despolarizantes/síntese química , gama-Ciclodextrinas , Animais , Cristalografia por Raios X , Ciclodextrinas/química , Ciclodextrinas/farmacologia , Diafragma/efeitos dos fármacos , Diafragma/inervação , Avaliação Pré-Clínica de Medicamentos , Cobaias , Interações Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Modelos Moleculares , Fármacos Neuromusculares não Despolarizantes/química , Rocurônio , Eletricidade Estática , Relação Estrutura-Atividade , SugammadexRESUMO
A novel approach to chiral succinimides and derived compounds has been developed that involves chiral lithium amide desymmetrisation of an N-ortho-tert-butylphenyl succinimide to generate a putative atropisomeric intermediate enolate, alkylation of which enables access to the lignan lactone (+)-hinokinin.
RESUMO
Liver X receptors (LXRs) are nuclear receptors that are central regulators of cholesterol homeostasis, and synthetic LXR agonists have shown promise as promoters of reverse cholesterol transport and anti-inflammatory agents. Here, we present three X-ray structures of three different agonists bound to the ligand binding domain of LXRalpha. These compounds are GW3965, F(3)methylAA, and a benzisoxazole urea, and we show that these diverse chemical scaffolds address common structural themes, leading to high binding affinity for LXR. Our structures show the LXRalpha ligand binding domain in its homodimeric form, an arrangement previously thought to be stereochemically difficult. A comparison with existing structures of the LXRbeta homodimer and LXRalpha:RXR (retinoid X receptor) heterodimers explains differences in dimer affinity and leads us to propose a model for allosteric activation in nuclear receptor dimers, in which an unactivated RXR partner provides an inhibitory tail wrap to the cofactor binding pocket of LXR.
Assuntos
Receptores Nucleares Órfãos/química , Transdução de Sinais , Benzoatos/química , Benzoatos/metabolismo , Benzilaminas/química , Benzilaminas/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Dimerização , Isoxazóis/química , Isoxazóis/metabolismo , Ligantes , Receptores X do Fígado , Modelos Moleculares , Receptores Nucleares Órfãos/metabolismo , Fenilacetatos/química , Fenilacetatos/metabolismo , Alinhamento de Sequência , Tiazóis/química , Tiazóis/metabolismoRESUMO
A number of water soluble bis-amino-2,6-dimethoxyphenyl ester derivatives were found to exhibit improved anaesthetic activity in mice relative to propofol 1. Of the analogues disclosed, 44 was further profiled in rodents and found to be a superior agent to propofol for the induction and maintenance of anaesthesia.