RESUMO
A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain.
Assuntos
Compostos de Anilina/química , Benzamidas/química , Receptor CB2 de Canabinoide/agonistas , Sulfonamidas/química , Compostos de Anilina/síntese química , Compostos de Anilina/farmacocinética , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Humanos , Microssomos Hepáticos/metabolismo , Dor/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinéticaRESUMO
Chiral recognition and resolution of methanobenzazocines was investigated by HPLC using polysaccharide, Pirkle-type, native and derivatized beta-cyclodextrin chiral stationary phases. Enantioseparation of phenyl substituted 2,6-methanobenzazocines was achieved with multiple chiral stationary phases throughout the classes described. Chiral resolution of the enantiomers of 1,5-methano-3-methyl-6-oxo-1,2,3,4,5,6-hexahydro-3-benzazocine was produced on both polysaccharide and Pirkle-type phases. In the case of 1,5-methano-3-methyl-6-phenyl-1,2,3,4,5,6-hexahydro-3-benzazocine only a dinitrophenyl substituted beta-cyclodextrin produced a separation of enantiomers.
Assuntos
Benzomorfanos/química , Cromatografia Líquida de Alta Pressão/métodos , EstereoisomerismoRESUMO
Non-selective cannabinoid ligands display a wide range of physiological effects including analgesic, anti-inflammatory, anti-convulsive and immuno-suppressive activities. A separation between therapeutic effects and undesirable CNS side effects may be accomplished by increasing the selectivity for the CB(2) receptor over the CB(1) receptor. There is considerable interest in developing new cannabimimetic compounds possessing preferentially high affinity for the CB(2) receptor as potential novel therapeutics for the treatment of inflammation and chronic pain. This review will summarize the literature on selective cannabinoid CB(2) receptor agonists from 2007 to the present, with special emphasis on SAR and medicinal chemistry strategies to improve physicochemical properties, metabolic stability and oral bioavailabilty of these inherently lipophilic ligands. Incorporating physicochemical property filters early in hit identification, concurrent screening of liver microsomal stability and addressing metabolic hot-spots through structural modifications or bio-isosteric replacements during lead optimization led to a number of structurally diverse CB(2) agonists with good oral bioavailability and in vivo efficacy in rodent models of pain.
Assuntos
Canabinoides/farmacologia , Receptor CB2 de Canabinoide/química , Receptor CB2 de Canabinoide/efeitos dos fármacos , Animais , Canabinoides/química , Canabinoides/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Isomerismo , Ligantes , Relação Quantitativa Estrutura-Atividade , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidoresRESUMO
Replacement of the phenyl ring in our previous (morpholinomethyl)aniline carboxamide cannabinoid receptor ligands with a pyridine ring led to the discovery of a novel chemical series of CB2 ligands. Compound 3, that is, 2,2-dimethyl-N-(5-methyl-4-(morpholinomethyl)pyridin-2-yl)butanamide was identified as a potent and selective CB2 agonist exhibiting in vivo efficacy after oral administration in a rat model of neuropathic pain.
Assuntos
Aminopiridinas/química , Morfolinas/química , Piridinas/química , Receptor CB2 de Canabinoide/agonistas , Administração Oral , Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Animais , Cães , Humanos , Masculino , Microssomos Hepáticos , Morfolinas/síntese química , Morfolinas/farmacologia , Dor/tratamento farmacológico , Ligação Proteica , Piridinas/síntese química , Piridinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
Recently sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Replacing the sulfonamide functionality and reversing the original carboxamide bond led to the discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB(2) agonists. Selective CB(2) agonist 31 (K(i)=2.7; CB(1)/CB(2)=190) displayed robust activity in a rodent model of postoperative pain.
Assuntos
Anti-Inflamatórios/química , Benzamidas/química , Receptor CB2 de Canabinoide/agonistas , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Descoberta de Drogas , Humanos , Dor Pós-Operatória/tratamento farmacológico , Ratos , Receptor CB2 de Canabinoide/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , TransfecçãoRESUMO
Previous research within our laboratories identified sulfamoyl benzamides as novel cannabinoid receptor ligands. Optimization of the amide linkage led to the reverse amide 40. The compound exhibited robust antiallodynic activity in a rodent pain model when administered intraperitoneally. Efficacy after oral administration was observed only when ABT, a cytochrome P450 suicide inhibitor, was coadministered.
Assuntos
Benzamidas/farmacologia , Receptor CB2 de Canabinoide/efeitos dos fármacos , Animais , Benzamidas/administração & dosagem , Benzamidas/química , Benzamidas/uso terapêutico , Dor/tratamento farmacológico , RoedoresRESUMO
Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB(2) receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB(2) receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects.
Assuntos
Benzamidas/uso terapêutico , Neuralgia/tratamento farmacológico , Receptor CB2 de Canabinoide/metabolismo , Sulfonamidas/uso terapêutico , Animais , Benzamidas/síntese química , Benzamidas/farmacologia , Sítios de Ligação , Relação Dose-Resposta a Droga , Ligantes , Camundongos , Modelos Animais , Modelos Químicos , Medição da Dor/efeitos dos fármacos , Ratos , Receptor CB2 de Canabinoide/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologiaRESUMO
Synthesis, in vitro biological evaluation, and structure-activity relationships of a biaryl cannabinoid mimetic 2 are reported. Variations in the substitution pattern yielded a number of agonists with low nanomolar affinity. Replacing the phenol group by a methyl morpholino acetate group led to compound 28, a 500-fold selective CB(2) receptor agonist.
Assuntos
Canabinoides/química , Canabinoides/síntese química , Química Farmacêutica/métodos , Ácidos Carboxílicos/química , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Hidrogênio/química , Ligação de Hidrogênio , Imunossupressores/química , Concentração Inibidora 50 , Cinética , Modelos Químicos , Parassimpatolíticos , Fenol/química , Ligação ProteicaRESUMO
10-Hydroxy-10,9-boroxarophenanthrenes were obtained as unexpected major products upon BBr(3)-mediated O-demethylation of 2-methoxybiaryls. The formation likely proceeds via intramolecular electrophilic aromatic cyclization of a reactive dibromoaryloxyborane intermediate. Essentially quantitative yields of 10-hydroxy-10,9-boroxarophenanthrenes were also obtained from 2-hydroxybiaryl and BCl(3)/AlCl(3) with use of a modified literature procedure. As synthetic intermediates, 10-hydroxy-10,9-boroxarophenanthrenes were efficiently converted to 3,4-benzocoumarins and triaryls through Pd-catalyzed CO insertion and Suzuki reaction.
RESUMO
Cationic phosphine ligands containing m-guanidinium phenyl substituents {Ph(3-n)P[C(6)H(4)-m-NHC(NH(2))(NMe(2))](n)}(n+) nCl(-) (n = 1-3) (17a-c) have been obtained by addition of dimethylcyanamide to the amino groups of tertiary (m-aminophenyl)phosphines in acidic medium. The tertiary (m-aminophenyl)phosphines Ph(3-n)P(C(6)H(4)-m-NH(2))(n) (4a-c) were prepared by reaction of (3-[N,N-bis(trimethylsilyl)amino]phenyl)magnesium chloride (1) with chlorophosphines Ph(3-n)PCl(n) followed by deprotection of the bis(trimethylsilyl)amino groups with methanol. Using a similar protected group synthesis as above, the secondary (m-aminophenyl)phosphine Ph(H)PC(6)H(4)-m-NH(2) (7) could be prepared as well. It may be employed as a building block for the syntheses of chiral bidentate phosphine ligands (11, 14, and 15) bearing m-aminophenyl substituents. The guanidinium phosphines 17b and 17c are readily soluble in water. A comparative study of 17b and 17c, the aryl alkyl guanidinium phosphines 18 and 19, and TPPTS (P(C(6)H(4)-m-SO(3)Na)(3)) in the aqueous phase palladium-catalyzed C-C coupling reaction between p-iodobenzoate and (trifluoroacetyl)propargylamine shows 17b to be of surmounting activity.