RESUMO
A two-step metal-halogen exchange and diastereoselective copper-mediated Michael addition onto a complex α,ß-unsaturated system has been developed and applied toward the synthesis of bisaryl Nrf2 activators. Optimization of metal-halogen exchange using (n-Bu)3MgLi allowed for the preparation of custom aryl-functionalized magnesiate reagents at noncryogenic temperatures. Following transmetalation, these reagents were used in highly diastereoselective Michael addition reactions.
RESUMO
GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors 1 and 2. Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CLu, Vdssu, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdssu and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdssu in addition to bulk physicochemical properties. Optimization of CLu within the series was guided by in vitro metabolite identification, and the poor FaSSIF solubility imparted by the crystalline properties of the pyrrolidine diol scaffold was improved by the introduction of a charged moiety to enable excellent exposure from high crystalline doses. GSK3527497 is a preclinical candidate suitable for oral and iv administration that is projected to inhibit TRPV4 effectively in patients from a low daily clinical dose.
Assuntos
Pirrolidinas/química , Sulfonamidas/química , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Animais , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Concentração Inibidora 50 , Pirrolidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Canais de Cátion TRPV/metabolismoRESUMO
Pulmonary edema is a common ailment of heart failure patients and has remained an unmet medical need due to dose-limiting side effects associated with current treatments. Preclinical studies in rodents have suggested that inhibition of transient receptor potential vanilloid-4 (TRPV4) cation channels may offer an alternative-and potentially superior-therapy. Efforts directed toward small-molecule antagonists of the TRPV4 receptor have led to the discovery of a novel sulfone pyrrolidine sulfonamide chemotype exemplified by lead compound 6. Design elements toward the optimization of TRPV4 activity, selectivity, and pharmacokinetic properties are described. Activity of leading exemplars 19 and 27 in an in vivo model suggestive of therapeutic potential is highlighted herein.
Assuntos
Edema Pulmonar/tratamento farmacológico , Pirrolidinas/farmacologia , Sulfonamidas/farmacologia , Sulfonas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonas/química , Sulfonas/farmacocinéticaRESUMO
A series of potent and receptor-selective cannabinoid-1 (CB1) receptor inverse agonists has been discovered. Peripheral selectivity of the compounds was assessed by a mouse tissue distribution study, in which the concentrations of a test compound in both plasma and brain were measured. A number of peripherally selective compounds have been identified through this process. Compound 2p was further evaluated in a 3-week efficacy study in the diet-induced obesity (DIO) mouse model. Beneficial effects on plasma glucose were observed from the compound-treated mice.
Assuntos
Agonismo Inverso de Drogas , Indazóis/farmacologia , Receptor CB1 de Canabinoide/agonistas , Animais , Indazóis/química , Indazóis/farmacocinética , Camundongos , Receptor CB2 de Canabinoide/agonistasRESUMO
Peripherally restricted CB1 receptor inverse agonists hold potential as useful therapeutics to treat obesity and related metabolic diseases without causing undesired CNS-mediated adverse effects. We identified a series of tetrahydropyrazolo[4,3-c]pyridine derivatives as potent and highly peripherally selective CB1 receptor inverse agonists. This discovery was achieved by introducing polar functional groups into the molecule, which increase the topological polar surface area and reduce its brain-penetrating ability.
Assuntos
Antagonistas de Receptores de Canabinoides/química , Antagonistas de Receptores de Canabinoides/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Antagonistas de Receptores de Canabinoides/farmacocinética , Agonismo Inverso de Drogas , Humanos , Masculino , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/farmacocinética , Distribuição TecidualRESUMO
A series of arylglycine-based analogs was synthesized and tested for TRPM8 antagonism in a cell-based functional assay. Following structure-activity relationship studies in vitro, a number of compounds were identified as potent TRPM8 antagonists and were subsequently evaluated in an in vivo pharmacodynamic assay of icilin-induced 'wet-dog' shaking in which compound 12 was fully effective. TRPM8 antagonists of the type described here may be useful in treating pain conditions wherein cold hypersensitivity is a dominant feature.
Assuntos
Glicina/farmacologia , Canais de Cátion TRPM/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glicina/análogos & derivados , Glicina/química , Células HEK293 , Humanos , Estrutura Molecular , Pirimidinonas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Canais de Cátion TRPM/agonistasRESUMO
A series of benzothiophene-based phosphonates was synthesized and many analogs within the series were shown to be potent antagonists of the TRPM8 channel. The compounds were obtained as a racemic mixture in 5 synthetic steps, and were tested for TRPM8 antagonist activity in a recombinant, canine TRPM8-expressing cell line using a fluorometric imaging plate reader (FLIPR) assay. Structure-activity relationships were developed initially by modification of the core structure and subsequently by variation of the aromatic substituents and the phosphonate ester. Compound 9l was administered intraperitoneally to rats and demonstrated engagement of the TRPM8 target in both prevention and reversal-modes in an icilin-induced 'wet-dog' shake model.
Assuntos
Desenho de Fármacos , Organofosfonatos/síntese química , Canais de Cátion TRPM/antagonistas & inibidores , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Cães , Concentração Inibidora 50 , Estrutura Molecular , Organofosfonatos/química , Organofosfonatos/farmacologia , Ligação Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
A series of aminoindane derivatives were synthesized and shown to be potent PPARalpha agonists. The compounds were obtained as racemates in 12 steps, and tested for PPARalpha activation and PPARalpha mediated induction of the HD gene. SAR was developed by variation to the core structure as shown within. Oral bioavailability was demonstrated in a Sprague-Dawley rat, while efficacy to reduce plasma triglycerides and plasma glucose was demonstrated in db/db mice.
Assuntos
Butiratos/síntese química , Butiratos/farmacologia , Indanos/síntese química , Indanos/farmacologia , PPAR alfa/agonistas , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia , Aminoácidos/química , Animais , Butiratos/química , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Indanos/química , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/químicaRESUMO
1. Antagonists of the V(2) vasopressin (AVP) receptor are aquaretic agents, inhibiting water resorption without stimulating electrolyte excretion. In this set of experiments, a novel V(2) receptor antagonist, RWJ-351647, was characterized in vitro and in vivo. 2. RWJ-351647 displaced (3)H-AVP binding from cloned human V(2) and V(1A) receptors with Ki values of 1 nmol/L and 24 nmol/L. In assays using transfected HEK293 cells expressing either human or rat V(2) receptors, RWJ-351647 inhibited AVP-induced cAMP accumulation with Ki values of 3 nmol/L and 6 nmol/L, respectively. 3. RWJ-351647 was very selective in binding assays and showed only weak functional antagonist activity at either the cloned human V(1B) and oxytocin receptors or the human platelet V(1A) receptor. No agonist activity was seen with the compound at any receptor. 4. Pharmacokinetic studies in rats showed RWJ-351647 to be 41.9% bioavailable after a single oral administration. After repeated daily dosing over 5 days, the oral bioavailability remained at 43.9% with no change in the compound peak plasma levels or clearance rate. 5. In efficacy studies, RWJ-351647 increased urine output and decreased urine osmolality with oral doses as low as 0.1 mg/kg and 1.0 mg/kg in rats and cynomolgus monkeys, respectively. In a multiple dose study in primates, RWJ-351647 maintained a consistent aquaretic effect over 10 days without increasing sodium or potassium excretion. 6. In summary, RWJ-351647 was shown to be a selective and potent V(2) receptor antagonist with sustainable aquaretic activity in both rats and primates. The preclinical data suggest that RWJ-351647 is a potent and effective aquaretic agent with potential for use in diseases characterized by water retention.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzodiazepinas/farmacologia , Animais , Benzodiazepinas/farmacocinética , Linhagem Celular , Feminino , Hematócrito , Humanos , Macaca fascicularis , Masculino , Concentração Osmolar , Ratos , Ratos Sprague-Dawley , Receptores de Ocitocina/efeitos dos fármacos , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
Vasopressin receptor antagonists can elicit ion-sparing diuretic effects (i.e., aquaresis) in vivo by blunting the action of the circulating hypophyseal hormone arginine vasopressin. We have identified two new series of basic tricyclic benzodiazepines, represented by general structure 1, which contain compounds that bind with high affinity to human V2 receptors. For example, (S)-(+)-8 and 5 are potent and selective V2 receptor antagonists with pronounced aquaretic activity in rats on oral administration.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzodiazepinas/farmacologia , Diuréticos/síntese química , Administração Oral , Animais , Benzodiazepinas/síntese química , Diuréticos/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Oxazinas/química , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiazinas/químicaRESUMO
The use of a multiplex mimetic assay led us to identify 1,4-dihydropyrimidines with potent and selective calcitonin receptor mimetic activity. Subsequent modification of the dihydropyrimidine scaffold led to a series of molecules that were efficacious in a neonatal mouse calvaria in vitro model. Dihydropyrimidine 5h, in particular, was identified as a calcitonin mimetic (EC(50)=6 microM), active in-vivo in the Weanling rat model when administered subcutaneously.
Assuntos
Calcitonina/química , Calcitonina/fisiologia , Di-Hidropiridinas/química , Mimetismo Molecular/fisiologia , Pirimidinas/química , Animais , Calcitonina/urina , Linhagem Celular , Di-Hidropiridinas/farmacologia , Di-Hidropiridinas/urina , Humanos , Pirimidinas/farmacologia , Pirimidinas/urina , RatosRESUMO
A series of novel 3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indoles was synthesized and tested for vasopressin receptor antagonist activity. We identified compounds with high affinity for the human V2 receptor and good selectivity over the human V1a receptor. Compound 6c bound to V2 receptors with an IC(50) value of 20 nM, had >100-fold selectivity over V1a receptors, and inhibited cAMP formation in a cellular V2 functional assay with an IC(50) value of 70 nM.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Azepinas/síntese química , Azepinas/farmacologia , Linhagem Celular , AMP Cíclico/antagonistas & inibidores , AMP Cíclico/biossíntese , Humanos , Concentração Inibidora 50 , Ensaio Radioligante , Receptores de Vasopressinas/genética , Relação Estrutura-Atividade , TransfecçãoRESUMO
We present the results of a study using vibrational circular dichroism (VCD) for (+)-1, which furnished an unambiguous determination of its absolute configuration as S. The most abundant conformation of (+)-1 in CDCl(3) solution was also established.