RESUMO
SAR around non-peptidic potent bombesin receptor subtype-3 (BRS-3) agonist lead 2 is presented. Attempts to replace the carboxylic acid with heterocyclic isosteres to improve oral bioavailability and brain penetration are described.
Assuntos
Fármacos Antiobesidade/síntese química , Imidazóis/química , Receptores da Bombesina/agonistas , Administração Oral , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Encéfalo/metabolismo , Humanos , Imidazóis/síntese química , Imidazóis/uso terapêutico , Camundongos , Obesidade/tratamento farmacológico , Ratos , Receptores da Bombesina/metabolismo , Relação Estrutura-AtividadeRESUMO
This Letter describes a series of potent and selective BRS-3 agonists containing a biarylethylimidazole pharmacophore. Extensive SAR studies were carried out with different aryl substitutions. This work led to the identification of a compound 2-{2-[4-(pyridin-2-yl)phenyl]ethyl}-5-(2,2-dimethylbutyl)-1H-imidazole 9 with excellent binding affinity (IC(50)=18 nM, hBRS-3) and functional agonist activity (EC(50)=47 nM, 99% activation). After oral administration, compound 9 had sufficient exposure in diet induced obese mice to demonstrate efficacy in lowering food intake and body weight via BRS-3 activation.
Assuntos
Imidazóis/química , Imidazóis/uso terapêutico , Obesidade/tratamento farmacológico , Receptores da Bombesina/agonistas , Receptores da Bombesina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Imidazóis/farmacocinética , Camundongos , Ratos , Relação Estrutura-AtividadeRESUMO
We report SAR studies on a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead series derived from high-throughput screening hit RY-337. This effort led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3.
Assuntos
Descoberta de Drogas , Imidazóis/química , Imidazóis/farmacologia , Receptores da Bombesina/agonistas , Animais , Disponibilidade Biológica , Humanos , Imidazóis/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The 8-(arylamino)-2'-deoxyguanosines, or C-8 adducts, are the major adducts formed by reaction of N-arylnitrenium ions derived from carcinogenic and mutagenic amines with 2'-deoxyguanosine (d-G) and guanosine residues of DNA. The hydrolysis kinetics of three C-8 adducts 1a-c were determined by UV and HPLC methods at 20 degrees C under acidic, neutral, and mildly alkaline conditions. At pH < 2 the dominant hydrolysis process is spontaneous cleavage of the C-N bond of the doubly protonated substrate, 1H(2)(+2) (Scheme 2). The C-8 adducts are 2- to 5-fold more reactive than d-G under these conditions. At 3 < pH < 6 the hydrolysis kinetics are dominated by cleavage of the C-N bond of the monoprotonated nucleoside 1H(+). Under these conditions the hydrolysis kinetics are accelerated by 40- to 1300-fold over that of d-G. The rate increase appears to be caused by a combination of steric acceleration of C-N bond cleavage and a decrease in the ionization constant of 1H(+), K(a1), due to the electron-donating properties of the arylamino C-8 substituent. Under neutral pH conditions a slow (k(obs) approximately 10(-8) s(-1) to 5 x 10(-7) s(-1)) spontaneous cleavage of the C-N bond of the neutral nucleoside, 1, occurs that has not been previously reported for simple purine nucleosides. Finally, under mildly alkaline conditions a process consistent with spontaneous decomposition of the anion 1(-) or OH(-)-induced decomposition of 1 is observed. The latter process has been observed for other purine nucleosides, including the closely related 1d, and involves nucleophilic attack of OH(-) on C-8 to cleave the imidazole ring of the purine.