RESUMO
An oral, peripherally restricted CB1/CB2 agonist could provide an interesting approach to treat chronic pain by harnessing the analgesic properties of cannabinoids but without the well-known central side effects. γ-Carbolines are a novel class of potent mixed CB1/CB2 agonists characterized by attractive physicochemical properties including high aqueous solubility. Optimization of the series has led to the discovery of 29, which has oral activity in a rat inflammatory pain model and limited brain exposure at analgesic doses, consistent with a lower risk of CNS-mediated tolerability issues.
Assuntos
Encéfalo/metabolismo , Canabinoides/agonistas , Carbolinas/química , Carbolinas/farmacologia , Analgésicos/química , Analgésicos/metabolismo , Analgésicos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Carbolinas/metabolismo , Linhagem Celular , Estabilidade de Medicamentos , Humanos , Estrutura Molecular , Dor/tratamento farmacológico , Ratos , SolubilidadeRESUMO
[reaction: see text] The addition of nucleophiles to 3-substituted pyridinium salts prepared from N-methylbenzamide and various pyridines has been investigated. Good to excellent regioselectivities favoring the 2,3-disubstituted 1,2-dihydropyridines were observed. The resulting 1,2-dihydropyridines led to the corresponding 2,3-disubstituted pyridines upon treatment with Mn(OAc)3/NaIO4. This methodology was also successfully applied to the enantioselective syntheses of (-)-L-733,061 and (-)-CP-99,994, two members of a new class of highly potent, nonpeptide, Substance P antagonists.
Assuntos
Piperidinas/síntese química , Compostos de Piridínio/síntese química , Substância P/antagonistas & inibidores , Estrutura Molecular , Piperidinas/química , Piperidinas/farmacologia , Compostos de Piridínio/química , Compostos de Piridínio/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 µM). Compound 6s demonstrated free-plasma exposures above the IC50 (â¼50×) with a brain-to-plasma ratio of â¼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.
Assuntos
Cognição/efeitos dos fármacos , Ciclopropanos/síntese química , Antagonistas dos Receptores Histamínicos H3/síntese química , Piperazinas/síntese química , Receptores Histamínicos H3/metabolismo , Compostos de Espiro/síntese química , Animais , Azetidinas/síntese química , Azetidinas/farmacocinética , Azetidinas/farmacologia , Células CHO , Permeabilidade da Membrana Celular , Cricetinae , Cricetulus , Ciclopropanos/farmacocinética , Ciclopropanos/farmacologia , Cães , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Antagonistas dos Receptores Histamínicos H3/farmacologia , Humanos , Aprendizagem/efeitos dos fármacos , Células Madin Darby de Rim Canino , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Piperazinas/farmacocinética , Piperazinas/farmacologia , Piperidinas/síntese química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H3/genética , Reconhecimento Psicológico/efeitos dos fármacos , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The medicinal chemistry subgroup of the American Chemical Society's Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PR) offers a perspective on the current state of environmentally sustainable practices in medicinal chemistry with the aim of sharing best practices more widely and highlighting some potential future developments.