RESUMO
The dysregulation of arginine vasopressin (AVP) release and activation of vasopressin V(1A) and V(2) receptors may play a role in disease. The in vitro and in vivo pharmacology of RWJ-676070, a potent, balanced antagonist of both the V(1A) and V(2) receptors is described. RWJ-676070 binding and intracellular functional antagonist activity was characterized using cells expressing V(1A), V(1B) or V(2) receptors. Its inhibition of V(1A) receptor-mediated contraction of vascular rings and platelet aggregation was determined. V(2) receptor-medated aquaresis was determined in rats, dogs and monkeys. V(1A) receptor-mediated inhibitory activity was assessed in vivo in a vasopressin-induced hypertension model and in normotensive rats and in two hypertensive rat models. RWJ-676070 inhibited AVP binding to human V(1A) and V(2) receptors (Ki=1 and 14 nM, respectively). RWJ-676070 inhibited V(1A) receptor-induced intracellular calcium mobilization and V(2) receptor-induced cAMP accumulation with Ki values of 14 nM and 13 nM, respectively. The compound was slightly less potent against rat V(1A) receptors. RWJ-676070 inhibited V(1A) receptor-mediated vasoconstriction in rat and dog vascular rings and AVP-induced human platelet aggregation. Dose dependent aquaresis was demonstrated in rats, dogs and monkeys following oral administration. RWJ-676070 inhibited AVP-induced hypertension in rats but had no effect on arterial pressure in normotensive and spontaneously hypertensive rats but did decrease arterial pressure in Dahl, salt-sensitive hypertensive rats. RWJ-676070 is a new, potent antagonist of V(1A) and V(2) receptors that may be useful for treatment of diseases benefiting from balanced inhibition of both V(1A) and V(2) receptors.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzazepinas/farmacologia , Compostos de Espiro/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/tratamento farmacológico , Técnicas In Vitro , Macaca fascicularis , Masculino , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Vasoconstrição , Vasopressinas/farmacologiaRESUMO
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
We have continued to explore spirobenzazepines as vasopressin receptor antagonists to follow up on RWJ-339489 (2), which had advanced into preclinical development. Further structural modifications were pursued to find a suitable backup compound for human clinical studies. Thus, we identified carboxylic acid derivative 3 (RWJ-676070; JNJ-17158063) as a potent, balanced vasopressin V(1a)/V(2) receptor antagonist with favorable properties for clinical development. Compound 3 is currently undergoing human clinical investigation.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Benzazepinas/química , Compostos de Espiro/química , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/farmacocinética , Benzazepinas/administração & dosagem , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Ratos , Ratos Long-Evans , Receptores de Vasopressinas/metabolismo , Receptores de Vasopressinas/fisiologia , Compostos de Espiro/administração & dosagem , Compostos de Espiro/metabolismo , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Vasopressinas/metabolismoRESUMO
A series of benzoxazinones has been synthesized and tested for PPARgamma agonist activity. Synthetic approaches were developed to provide either racemic or chiral compounds. In vitro functional potency could be measured through induction of the aP2 gene, a target of PPARgamma. These studies revealed that compounds with large aliphatic chains at the nitrogen of the benzoxazinone were the most potent. Substitution of the chain was tolerated and in many cases enhanced the in vitro potency of the compound. Select compounds were further tested for metabolic stability, oral bioavailability in rats, and efficacy in db/db mice after 11 days of dosing. In vivo analysis with 13 and 57 demonstrated that the series has potential for the treatment of type 2 diabetes.
Assuntos
Amidas/síntese química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Oxazinas/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Amidas/química , Amidas/farmacologia , Animais , Disponibilidade Biológica , Sistema Enzimático do Citocromo P-450/metabolismo , Estabilidade de Medicamentos , Feminino , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Oxazinas/química , Oxazinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Diabetes mellitus has been declared to be at an epidemic level by the World Health Organization. The syndrome is characterised as either Type I (insulin-dependent) or Type II (non-insulin-dependent) diabetes mellitus. Impaired glucose tolerance for extended periods of time results in serious complications such as kidney damage and impaired blood circulation and is the main cause for blindness and amputations in patients with diabetes. A combination of life-style change, dietary change and oral medications can treat Type II diabetes mellitus effectively and prevent long-term complications. Combination therapy appears to be the most effective approach in controlling blood glucose levels. This review updates the progress made in medicinal chemistry towards promising biological targets, with the development of a new generation of small molecules having improved efficacy and safety profiles.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Inibidores Enzimáticos/uso terapêutico , Humanos , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/metabolismo , Receptores X de Retinoides , Fatores de Transcrição/agonistas , Fatores de Transcrição/metabolismoRESUMO
The in-vitro biotransformation of a new calcium-mimetic agent and benzenemethanamine analogue, RWJ-68025, was studied after incubation with rat and human hepatic S9 fractions in the presence of an NADPH-generating system. Unchanged RWJ-68025 (44-48% of the sample) plus 12 metabolites were profiled, quantified, and tentatively identified on the basis of API (ionspray)-MS and MS/MS data, and ethyl derivatization for phenolic and carboxylic metabolites. Four metabolic pathways for RWJ-68025 were proposed: pathway 1, O-demethylation; pathway 2, phenyl oxidation; pathway 3, methyl oxidation; and pathway 4, N-dealkylation/acetylation. Pathway 1 formed a major metabolite, O-desmethyl-RWJ-68025 (M1; RWJ-68311; 26% in rat; 16% in human fraction). Pathway 2 produced one major (M2; 12-17% in rat and human fraction) and two minor phenolic metabolites (M4 and M5; all <1% in both species), and in conjunction with step 1, formed hydroxy-M1 (M3; 4-5% in both species). Pathways 3 and 4 formed seven minor oxidized metabolites (M6-M12). RWJ-68025 was extensively metabolized in the rat and human hepatic S9 fractions.
Assuntos
Cálcio/metabolismo , Ciclopropanos/metabolismo , Fígado/metabolismo , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Biotransformação , Cálcio/agonistas , Cálcio/química , Cálcio/farmacologia , Ciclopropanos/análise , Ciclopropanos/química , Humanos , Masculino , Mimetismo Molecular , RatosRESUMO
Lysosomal enzymes are responsible for the degradation of a wide variety of glycolipids, oligosaccharides, proteins, and glycoproteins. Inherited mutations in the genes that encode these proteins can lead to reduced stability of newly synthesized lysosomal enzymes. While often catalytically competent, the mutated enzymes are unable to efficiently pass the quality control mechanisms of the endoplasmic reticulum, resulting in reduced lysosomal trafficking, substrate accumulation, and cellular dysfunction. Pharmacological chaperones (PCs) are small molecules that bind and stabilize mutant lysosomal enzymes, thereby allowing proper cellular translocation. Such compounds have been shown to increase enzyme activity and reduce substrate burden in a number of preclinical models and clinical studies. In this Perspective, we review several of the lysosomal diseases for which PCs have been studied and the SAR of the various classes of molecules.
Assuntos
Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Chaperonas Moleculares/uso terapêutico , Linhagem Celular , Glicolipídeos/metabolismo , Humanos , Relação Estrutura-AtividadeRESUMO
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor family of ligand-activated transcription factors. It plays an important role in the regulation of genes involved in lipid metabolism and transport. Compound A is a potent and orally active PPARalpha agonist that activated both human and rat PPARalpha receptors. The compound induced the expression of genes involved in fatty acid metabolism in a rodent hepatoma cell line and in the liver of db/db mouse. The ability of compound A to stimulate fatty acid beta-oxidation was demonstrated in human hepatocytes and human skeletal muscle cells, which confirmed a functional activation of PPARalpha-mediated activities. Compound A was shown to be a more potent and efficacious antidyslipidemic agent in atherogenic rat and db/db mouse models as compared with fenofibrate. The increase in high-density lipoprotein cholesterol levels by compound A was at least partially due to an increase in serum apolipoprotein A-I protein concentrations in human PPARalpha transgenic mouse. The triglyceride-lowering effect was further confirmed in a higher species, obese dog models. In addition, compound A dose-dependently ameliorated hyperglycemia and hyperinsulinemia, and improved glucose tolerance in db/db mice. In a diet-induced obesity mouse model, compound A decreased body weight mainly by increasing energy expenditure and reducing fat deposition. In conclusion, the novel and potent PPARalpha agonist improves lipid profile, insulin sensitivity, and energy balance in animal models.
Assuntos
Dislipidemias/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Indanos/farmacologia , Resistência à Insulina , PPAR alfa/agonistas , Compostos de Fenilureia/farmacologia , Animais , Apolipoproteína A-I/sangue , Cães , Relação Dose-Resposta a Droga , Ácidos Graxos/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperinsulinismo/tratamento farmacológico , Indanos/uso terapêutico , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Oxirredução , Compostos de Fenilureia/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
A series of indole-O-glucosides and C-glucosides was synthesized and evaluated in SGLT1 and SGLT2 cell-based functional assays. Compounds 2a and 2o were identified as potent SGLT2 inhibitors and screened in ZDF rats.
Assuntos
Glucosídeos/química , Glucosídeos/farmacologia , Indóis/química , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Diabetes Mellitus Experimental/urina , Glucose/metabolismo , Glucosídeos/síntese química , Estrutura Molecular , Ratos , Ratos Zucker , Transportador 1 de Glucose-Sódio/antagonistas & inibidoresRESUMO
A series of benzo-fused heteroaryl-O-glucosides was synthesized and evaluated in SGLT1 and 2 cell-based functional assays. Indole-O-glucoside 10a and benzimidazole-O-glucoside 18 exhibited potent in vitro SGLT2 inhibitory activity.
Assuntos
Glucosídeos/química , Glucosídeos/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose , Glucosídeos/síntese química , Humanos , Estrutura MolecularRESUMO
A series of 3-anilino-quinoxalinones has been identified as a new class of glycogen phosphorylase inhibitors. The lead compound 1 was identified through high throughput screening as well as through pharmacophore-based electronic screening. Modifications were made to the scaffold of 1 to produce novel analogues, some of which are 25 times more potent than the lead compound.
Assuntos
Glicogênio Fosforilase/antagonistas & inibidores , Hipoglicemiantes/síntese química , Animais , Glicemia/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Hipoglicemiantes/farmacocinética , Concentração Inibidora 50 , Camundongos , Camundongos Obesos , Quinoxalinas , Relação Estrutura-AtividadeRESUMO
A series of glucose conjugates was synthesized and tested for inhibition of SGLT1 and SGLT2. The core structure was derived from compound 1a. Modification of the benzofuran moiety and 4'-substituent of the phenyl ring in compound 1a improved selectivity at SGLT2. Select compounds were compared to 1a in metabolic stability and in vivo efficacy studies.
Assuntos
Chalcona/análogos & derivados , Chalcona/síntese química , Proteínas de Transporte de Monossacarídeos/antagonistas & inibidores , Animais , Células Cultivadas , Chalcona/farmacologia , Chalconas , Estabilidade de Medicamentos , Glicosilação , Humanos , Técnicas In Vitro , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Microssomos Hepáticos/metabolismo , Florizina/síntese química , Florizina/farmacologia , Ratos , Ratos Zucker , Transportador 1 de Glucose-Sódio , Transportador 2 de Glucose-Sódio , Relação Estrutura-AtividadeRESUMO
A number of 2,5-disubstituted benzothiazepines were synthesized and screened for their ability to inhibit arginine vasopressin binding to the human V(2) and V(1a) receptor subtypes. The more active compounds were subsequently analyzed for their antagonist activity in in vitro functional assays. The SAR showed a preference for an acidic unit appended from the benzothiazepine scaffold. This substitution pattern afforded the most potent and selective analogues in the series. The carboxymethyl analogue 4, showed a 140-fold greater selectivity for the V(2) over the V(1a) receptor in the binding assay. In the cell-based functional assays this analogue was a potent and selective antagonist of the V(2) receptor. The in vitro SAR of the series and a description of the in vivo studies around compound 4 is described.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Dibenzotiazepinas/síntese química , Dibenzotiazepinas/farmacologia , Animais , Azepinas/síntese química , Azepinas/química , Azepinas/farmacologia , Benzamidas/síntese química , Benzamidas/química , Benzamidas/farmacologia , Benzazepinas/síntese química , Benzazepinas/química , Benzazepinas/farmacologia , Diurese/efeitos dos fármacos , Desenho de Fármacos , Cinética , Masculino , Pirróis , Ratos , Relação Estrutura-AtividadeRESUMO
A series of benzoxazinones was synthesized as PPARgamma agonists. The compounds were obtained in seven steps, and SAR was developed by variations to the core shown below. The compounds were tested as functional agonists in the induction of the aP2 gene in preadipocytes, and the most potent compound in the series has an EC(50)=0.51 microM. The potency was further confirmed through a PPAR-Gal4 construct. Efficacy has been demonstrated in the db/db mouse model of hyperglycemia.
Assuntos
Oxazinas/síntese química , Oxazinas/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Complexo 2 de Proteínas Adaptadoras/biossíntese , Complexo 2 de Proteínas Adaptadoras/genética , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Área Sob a Curva , Disponibilidade Biológica , Expressão Gênica/efeitos dos fármacos , Meia-Vida , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Técnicas In Vitro , Indicadores e Reagentes , Luciferases/genética , Camundongos , Microssomos Hepáticos/metabolismo , Ratos , Relação Estrutura-Atividade , Frações SubcelularesRESUMO
A series of substituted spirobenzazepines was prepared and evaluated as V(1a) and V(2) dual vasopressin receptor antagonists. Compounds 7p and 7q have been shown to be not only potent inhibitors of vasopressin receptors, but also have exhibited an excellent overall pharmaceutical suitability profile.