RESUMO
In a search for novel small molecule calcium-sensing receptor (CaSR) antagonists as oral bone anabolic agents, we discovered dihydrobenzofuran cyclopropane carboxylic acid derivatives, such as 12f (IC50=27.6nM), are highly potent calcium-sensing receptor antagonists. Studies in rats established that compound 12f stimulates parathyroid hormone (PTH) release in a fast-acting, pulsatile manner.
Assuntos
Benzofuranos/química , Ciclopropanos/metabolismo , Osteoporose/tratamento farmacológico , Receptores de Detecção de Cálcio/antagonistas & inibidores , Administração Oral , Animais , Benzofuranos/metabolismo , Benzofuranos/farmacocinética , Benzofuranos/uso terapêutico , Ciclopropanos/química , Ciclopropanos/farmacocinética , Ciclopropanos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Feminino , Meia-Vida , Osteoporose/patologia , Hormônio Paratireóideo/sangue , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de Detecção de Cálcio/metabolismo , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and structure-activity relationship (SAR) for a series of ß-substituted 3-(4-aryloxyaryl)propanoic acid GPR40 agonists is described. Systematic replacement of the pendant aryloxy group led to identification of potent GPR40 agonists. In order to identify candidates suitable for in vivo validation of the target, serum shifted potency and pharmacokinetic properties were determined for several compounds. Finally, further profiling of compound 7 is presented, including demonstration of enhanced glucose tolerance in an in vivo mouse model.
Assuntos
Hipoglicemiantes/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Propionatos/síntese química , Propionatos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Ciclização , Modelos Animais de Doenças , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Propionatos/química , Propionatos/farmacocinéticaRESUMO
Probing with tool molecules, and by modeling and X-ray crystallography the binding modes of two structurally distinct series of DPP-4 inhibitors led to the discovery of a rare aromatic fluorine H-bond and the spatial requirement for better biaryl binding in the DPP-4 enzyme active site. These newly found binding elements were successfully incorporated into novel DPP-4 inhibitors.
Assuntos
Dipeptidil Peptidase 4/química , Sítios de Ligação , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Inibidores da Dipeptidil Peptidase IV , Desenho de Fármacos , Flúor/química , Glicina/química , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Modelos Químicos , Modelos Teóricos , Conformação Molecular , Software , beta-Alanina/químicaRESUMO
Diaryl-(4-piperidinyl)-pyrrole derivatives bearing cyclic amine substituents have been synthesized and evaluated as anticoccidial agents. Improvements in potency of Et-PKG inhibition, such as azetidine derivative 3a, and broad spectrum anticoccidial activities in feed, such as morpholine derivative 8c, have been achieved.
Assuntos
Coccidiose/tratamento farmacológico , Coccidiostáticos/farmacologia , Eimeria/efeitos dos fármacos , Pirróis/farmacologia , Animais , Galinhas , Coccidiostáticos/síntese química , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Eimeria/enzimologia , Feminino , Estrutura Molecular , Oocistos/efeitos dos fármacos , Oocistos/fisiologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/síntese química , Pirróis/química , Relação Estrutura-AtividadeRESUMO
We report new SSTR5 antagonists with enhanced potency, subtype selectivity, and minimal off-target activities as compared to previously reported compounds. Starting from the reported SSTR5 antagonist 1, we systematically surveyed changes in the central core and head piece while maintaining the diphenyl tail group constant. From this study the azaspirodecanone 10 emerged as a new highly potent and selective SSTR5 antagonist. Compound 10 lowered glucose excursion by 94% in an oral glucose tolerance test (OGTT) in mice following a 3 mg/kg oral dose. The compound increased both total and active circulating incretin hormone GLP-1 levels in mice at a dose of 10 mg/kg. A synergistic effect was also demonstrated when compound 10 was coadministered with a DPP-4 inhibitor, substantially increasing circulating active GLP-1[7-36] amide and insulin in response to a glucose challenge.
RESUMO
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
Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
RESUMO
Following the discovery of N-acyl-1,4-diazepan-2-one as a novel pharmacophore for potent and selective DPP-4 inhibitors, optimization of this new lead with different substitution on the seven-membered ring resulted in several highly potent and selective, orally bioavailable, and efficacious DPP-4 inhibitors, such as 3R-methyl-1-cyclopropyl-1,4-diazepan-2-one derivative 9i (DPP-4 IC(50)=8.0 nM) and 3R,6R-dimethyl-1,4-diazepan-2-one derivative 14a (DPP-4 IC(50)=9.7 nM).
Assuntos
Azepinas/síntese química , Química Farmacêutica/métodos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Administração Oral , Animais , Azepinas/farmacologia , Desenho de Fármacos , Concentração Inibidora 50 , Masculino , Camundongos , Modelos Químicos , Conformação Molecular , Ratos , Ratos Sprague-DawleyRESUMO
Diaryl imidazo[1,2-a]pyridine derivatives, such as 6a and 7i, have been synthesized and found to be potent inhibitors of parasite PKG activity. The most potent compounds are the 7-isopropylaminomethyl analog 6a and 2-isopropylamino analog 7i. These compounds are also fully active in in vivo assay as anticoccidial agents at 25 ppm in feed.
Assuntos
Coccidiose/tratamento farmacológico , Coccidiostáticos/farmacologia , Imidazóis/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Piridinas/farmacologia , Animais , Química Farmacêutica/métodos , Coccidiostáticos/química , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Desenho de Fármacos , Eimeria tenella , Modelos Químicos , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Replacement of the triazolopiperazine ring of sitagliptin (DPP-4 IC(50)=18nM) with 3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one gave dipeptidyl peptidase IV (DPP-4) inhibitor 1 which is potent (DPP-4 IC(50)=2.6nM), selective, and efficacious in an oral glucose tolerance test in mice. It was selected for extensive preclinical development as a potential back-up candidate to sitagliptin.
Assuntos
Azepinas/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV , Hipoglicemiantes/química , Inibidores de Proteases/química , Animais , Azepinas/uso terapêutico , Cristalografia por Raios X , Dipeptidil Peptidase 4/química , Hipoglicemiantes/uso terapêutico , Inibidores de Proteases/uso terapêutico , Conformação Proteica , Pirazinas/química , Pirazinas/uso terapêutico , Ratos , Ratos Endogâmicos , Fosfato de Sitagliptina , Triazóis/química , Triazóis/uso terapêuticoRESUMO
Compounds 10a-10d and 10i are very potent inhibitors of Eimeria tenella cGMP-dependent protein kinase (0.081-0.32 nM) and are very efficacious antiparasitic agents in vivo when administered to chickens at 12.5-25 ppm levels in the feed.
Assuntos
Coccidiostáticos/síntese química , Coccidiostáticos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Piridinas/química , Piridinas/síntese química , Piridinas/farmacologia , Animais , Coccidiostáticos/química , Eimeria/efeitos dos fármacos , Imidazóis/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
2-(4-Fluorophenyl)-3-(4-pyridinyl)-5-substituted pyrroles were prepared and evaluated as anticoccidial agents in both in vitro and in vivo assays. Among the compounds evaluated, the dimethylamine-substituted pyrrole 19a is the most potent inhibitor of Eimeria tenella PKG (cGMP-dependent protein kinase). Further SAR studies on the side chain of the 2-pyrrolidine nitrogen did not enhance in vivo anticoccidial activity.
Assuntos
Coccidiostáticos/síntese química , Coccidiostáticos/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Animais , Coccidiostáticos/química , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Eimeria tenella/efeitos dos fármacos , Eimeria tenella/enzimologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Pirróis/química , Relação Estrutura-AtividadeRESUMO
Compounds 10a (IC50 110 pM) and 21 (IC50 40 pM) are the most potent inhibitors of Eimeria tenella cGMP-dependent protein kinase activity reported to date and are efficacious in the in vivo antiparasitic assay when administered to chickens at 12.5 and 6.25 ppm levels in the feed. However, both compounds are positive in the Ames microbial mutagenesis assay which precludes them from further development as antiprotozoal agents in the absence of negative lifetime rodent carcinogenicity studies.
Assuntos
Antiprotozoários/síntese química , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Eimeria tenella/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Imidazóis/síntese química , Piridinas/síntese química , Ração Animal , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Galinhas , Coccidiose/tratamento farmacológico , Eimeria tenella/enzimologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Masculino , Estrutura Molecular , Testes de Mutagenicidade , Oocistos/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Piridinas/química , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Several analogs of 2,3-diaryl pyrroles were synthesized and evaluated as inhibitors of Eimeria tenella cGMP-dependent protein kinase and in in vivo anticoccidial assays. A 4-fluorophenyl group enhances both in vitro and in vivo activities. The most potent analogs are the 5-(N-methyl, N-ethyl, and N-methylazetidine methyl) piperidyl derivatives 12, 23, and 34. These compounds have a broad spectrum of activity. Based on the in vivo efficacy and cost of synthesis, the N-ethyl analog 23 was chosen as a novel anticoccidial agent for a field trial.
Assuntos
Coccidiostáticos/síntese química , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Proteínas de Protozoários/antagonistas & inibidores , Pirróis/síntese química , Animais , Disponibilidade Biológica , Galinhas , Coccidiose/tratamento farmacológico , Coccidiostáticos/farmacocinética , Coccidiostáticos/farmacologia , Eimeria , Meia-Vida , Concentração Inibidora 50 , Pirróis/farmacocinética , Pirróis/farmacologia , Relação Estrutura-AtividadeRESUMO
Diaryl-(4-piperidinyl)-pyrrole derivatives bearing hydroxylated N-alkyl substituents have been synthesized and evaluated as anticoccidial agents. High potency in Et-PKG inhibition and broad-spectrum anticoccidial activities have been observed on compounds, such as 4b and 5h, which are fully efficacious in vivo at 50 ppm in feed.