RESUMO
Previous drug discovery efforts identified classical PYK2 kinase inhibitors such as 2 and 3 that possess selectivity for PYK2 over its intra-family isoform FAK. Efforts to identify more kinome-selective chemical matter that stabilize a DFG-out conformation of the enzyme are described herein. Two sub-series of PYK2 inhibitors, an indole carboxamide-urea and a pyrazole-urea have been identified and found to have different binding interactions with the hinge region of PYK2. These leads proved to be more selective than the original classical inhibitors.
Assuntos
Quinase 2 de Adesão Focal/antagonistas & inibidores , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Ureia/farmacologia , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Quinase 2 de Adesão Focal/metabolismo , Células HEK293 , Humanos , Indóis/síntese química , Indóis/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Ratos , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/químicaRESUMO
We report the structure-activity relationships, design, and synthesis of the novel cannabinoid type 1 (CB1) receptor antagonist 3a (CP-945,598). Compound 3a showed subnanomolar potency at human CB1 receptors in binding (Ki = 0.7 nM) and functional assays (Ki = 0.12 nM). In vivo, compound 3a reversed cannabinoid agonist-mediated responses, reduced food intake, and increased energy expenditure and fat oxidation in rodents.
Assuntos
Piperidinas/farmacologia , Purinas/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Cães , Descoberta de Drogas , Metabolismo Energético , Gorduras/metabolismo , Oxirredução , Piperidinas/química , Purinas/química , Relação Estrutura-AtividadeRESUMO
A series of conformationally constrained bicyclic derivatives derived from SR141716 was prepared and evaluated as hCB(1)-R antagonists and inverse agonists. Optimization of the structure-activity relationships around the 2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one derivative 2a led to the identification of two compounds with oral activity in rodent feeding models (2h and 4a). Replacement of the PP group in 2h with other bicyclic groups resulted in a loss of binding affinity.
Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Comportamento Alimentar/efeitos dos fármacos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Sítios de Ligação , Comportamento Alimentar/fisiologia , Modelos Biológicos , Piperidinas/química , Pirazóis/química , Pirazolonas/química , Pirimidinonas/química , Receptor CB1 de Canabinoide/agonistas , Rimonabanto , Roedores , Relação Estrutura-AtividadeRESUMO
Novel pyrazolinone-piperidine dipeptide derivatives were synthesized and evaluated as growth hormone secretagogues (GHSs). Two analogues, capromorelin (5, CP-424391-18, hGHS-R1a K(i)=7 nM, rat pituicyte EC(50)=3 nM) and the des-methyl analogue 5c (hGHS-R1a K(i)=17 nM, rat pituicyte EC(50)=3 nM), increased plasma GH levels in an anesthesized rat model, with ED(50) values less than 0.05 mg/kg iv. Capromorelin showed enhanced intestinal absorption in rodent models and exhibited superior pharmacokinetic properties, including high bioavailabilities in two animal species [F(rat)=65%, F(dog)=44%]. This short-duration GHS was orally active in canine models and was selected as a development candidate for the treatment of musculoskeletal frailty in elderly adults.
Assuntos
Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Hormônio do Crescimento/metabolismo , Piperidinas/síntese química , Piperidinas/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Animais , Células Cultivadas , Fenômenos Químicos , Físico-Química , DNA Complementar/metabolismo , Dipeptídeos/farmacocinética , Cães , Desenho de Fármacos , Feminino , Meia-Vida , Humanos , Indicadores e Reagentes , Indóis/farmacologia , Espectroscopia de Ressonância Magnética , Piperidinas/farmacocinética , Hipófise/citologia , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Pirazóis/farmacocinética , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Solubilidade , Compostos de Espiro/farmacologiaRESUMO
New tert-butyl, picolyl and fluorinated analogues of capromorelin (3), a short-acting growth hormone secretagogue (GHS), were prepared as part of a program to identify long-acting GHSs that increase 24-h plasma IGF-1 levels. Compounds 4c and 4d (ACD LogD values >or=2.9) displayed extended plasma elimination half-lives in dogs, primarily due to high volumes of distribution, but showed weak GH secretagogue activities in rats (ED(50)s>10 mg/kg). A less lipophilic derivative 4 (ACD LogD=1.6) exhibited a shorter canine half-life, but stimulated GH secretion in two animal species. Repeat oral dosing of 4 in dogs for 29 days (6 mg/kg) resulted in a significant down-regulation of the post dose GH response and a 60 and 40% increase in IGF-1 levels relative to pre-dose levels at the 8- and 24-h post dose time points. Compound 4 (CP-464709-18) has been selected as a development candidate for the treatment of frailty.