RESUMO
Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.5 channel openers was explored. PF-05020182 (2) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 (2) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 (2) support further development as an adjunctive treatment of refractory epilepsy.
Assuntos
Descoberta de Drogas , Epilepsia/tratamento farmacológico , Ativação do Canal Iônico/efeitos dos fármacos , Canal de Potássio KCNQ2/metabolismo , Piperidinas/farmacologia , Pirimidinas/farmacologia , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Eletrochoque , Humanos , Canal de Potássio KCNQ2/agonistas , Microssomos/efeitos dos fármacos , Estrutura Molecular , Piperidinas/administração & dosagem , Piperidinas/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
We describe a novel series of inhibitors of the type 1 glycine transporter (GlyT1) as an approach to relieving the glutamatergic deficit that is thought to underlie schizophrenia. Synthesis and SAR follow-up of a series of octahydro-cyclopenta[c]pyrrole derivatives afforded potent in vitro inhibition of GlyT1 as well as in vivo activity in elevating CSF glycine. We also found that a 3-O(c-pentyl), 4-F substituent may serve as a surrogate for the widely used 3-trifluoromethoxy group, suggesting its application as an isostere for future medicinal chemistry studies.
Assuntos
Ciclopentanos/química , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Pirróis/química , Animais , Linhagem Celular , Ciclopentanos/farmacologia , Cães , Proteínas da Membrana Plasmática de Transporte de Glicina/fisiologia , Humanos , Microssomos/efeitos dos fármacos , Microssomos/fisiologia , Pirróis/farmacologiaRESUMO
We report the synthesis of a series of [3.2.1]azabicyclic biaryl ethers as selective agonists of alpha3- and alpha6-containing nicotinic receptors. In particular, compound 17a from this series is a potent alpha3beta4 and alpha6/4beta4 receptor agonist in terms of both binding and functional activity. Compound 17a also shows potent in vivo activity in CNS-mediated animal models that are sensitive to antipsychotic drugs. Compound 17a may thus be a useful tool for studying the role of alpha3beta4 and alpha6/4beta4 nicotinic receptors in CNS pharmacology.
Assuntos
Compostos Azabicíclicos/química , Agonistas Nicotínicos/química , Receptores Nicotínicos/química , Sulfonamidas/química , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/farmacologia , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologiaRESUMO
Sulfonamides, exemplified by 3a, were identified as highly selective EP(2) agonists. Lead optimization led to the identification of CP-533536, 7f, a potent and selective EP(2) agonist. CP-533536 demonstrated the ability to heal fractures when administered locally as a single dose in rat models of fracture healing.
Assuntos
Osteogênese/efeitos dos fármacos , Piridinas/química , Receptores de Prostaglandina E/agonistas , Animais , Masculino , Piridinas/administração & dosagem , Piridinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E/metabolismo , Receptores de Prostaglandina E Subtipo EP2 , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
Heptanoic acid lactams, exemplified by 2, were identified as highly selective EP4 agonists via high throughput screening. Lead optimization led to the identification of lactams with a 30-fold increase in EP4 potency in vitro. Compounds demonstrated robust bone anabolic effects when administered in vivo in rat models of osteoporosis.
Assuntos
Densidade Óssea/efeitos dos fármacos , Desenvolvimento Ósseo , Osso e Ossos/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Receptores de Prostaglandina E/agonistas , Animais , Feminino , Osteoporose , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP4RESUMO
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.
Assuntos
Piperidinas/farmacocinética , Pirazóis/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Cães , Hormônio do Crescimento/efeitos dos fármacos , Substâncias de Crescimento/metabolismo , Meia-Vida , Interações Hidrofóbicas e Hidrofílicas , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Masculino , Piperidinas/administração & dosagem , Piperidinas/síntese química , Pirazóis/administração & dosagem , Pirazóis/síntese química , Ratos , Ratos Wistar , 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.