RESUMO
Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased Vmax with unchanged Km), phenocopies the ability of protein kinase A (PKA) to activate PDE4 long isoforms endogenously, and requires a dimeric enzyme assembly, as adopted by long, but not by short (monomeric), PDE4 isoforms. Abnormally elevated levels of cAMP provide a critical driver of the underpinning molecular pathology of autosomal dominant polycystic kidney disease (ADPKD) by promoting cyst formation that, ultimately, culminates in renal failure. Using both animal and human cell models of ADPKD, including ADPKD patient-derived primary cell cultures, we demonstrate that treatment with the prototypical PDE4 activator compound lowers intracellular cAMP levels, restrains cAMP-mediated signaling events, and profoundly inhibits cyst formation. PDE4 activator compounds thus have potential as therapeutics for treating disease driven by elevated cAMP signaling as well as providing a tool for evaluating the action of long PDE4 isoforms in regulating cAMP-mediated cellular processes.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Animais , Linhagem Celular , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/efeitos dos fármacos , Cães , Ativação Enzimática/efeitos dos fármacos , Humanos , Células Madin Darby de Rim Canino , Fosforilação , Doenças Renais Policísticas/metabolismo , Isoformas de ProteínasRESUMO
Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.
Assuntos
Desenho de Fármacos , Indóis/síntese química , Neuralgia/tratamento farmacológico , Oxidiazóis/síntese química , Receptor CB1 de Canabinoide/agonistas , Animais , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Células CACO-2 , Humanos , Indóis/química , Indóis/farmacocinética , Camundongos , Oxidiazóis/química , Oxidiazóis/farmacocinética , RatosRESUMO
Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1.
Assuntos
Compostos Heterocíclicos/química , Indóis/química , Receptor CB1 de Canabinoide/agonistas , Tiadiazóis/química , Animais , Desenho de Fármacos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Indóis/síntese química , Indóis/farmacocinética , Camundongos , Microssomos/metabolismo , Modelos Moleculares , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/farmacocinéticaRESUMO
Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.
Assuntos
Compostos Heterocíclicos/farmacocinética , Receptor CB1 de Canabinoide/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Descoberta de Drogas , Compostos Heterocíclicos/administração & dosagem , RatosRESUMO
We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.
Assuntos
Compostos Heterocíclicos/química , Indóis/química , Receptor CB1 de Canabinoide/agonistas , Tiazóis/química , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Camundongos , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinéticaRESUMO
Novel tricyclic indole-3-carboxamides were synthesized as structurally restricted analogs of bicyclic indoles, and found to be potent CB1 cannabinoid receptor agonists. The CB1 agonist activity depended on the absolute configuration of the chiral center of the tricyclic ring. The preferred enantiomer was more potent than the structurally unconstrained lead compound. Structure-activity relationships in the amide side chain of the indole C-3 position were also investigated.
Assuntos
Amidas/química , Indóis/química , Receptor CB1 de Canabinoide/agonistas , Amidas/síntese química , Amidas/farmacocinética , Animais , Desenho de Fármacos , Humanos , Camundongos , Microssomos/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
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-AtividadeRESUMO
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.