RESUMO
2-Trifluoromethyl-4-aminobenzimidazoles were previously identified by screening to be active antagonists of the gonadotropin releasing hormone receptor (GnRH-R). Structure activity relationships and diversity oriented synthesis are shown here in greater detail. 2-Substituted benzimidazoles were synthesized in parallel by the coupling of carboxylic acids with a latent intermediate diamine monomer to yield the desired benzimidazoles in fair yields. A catch and release strategy was employed as a product isolation technique, followed by RP-HPLC to obtain products of desired purity for biological evaluation. Two libraries were prepared and screened to determine the optimal substitution for inhibitory activity against GnRH-R. The initial library focused on substituted phenyl, pyridine, and thiophenes. The follow-up library focused on substitution patterns observed in the initial library members and generated compounds with IC(50) values lower than 100 nM at the GnRH-R.
Assuntos
Benzimidazóis/síntese química , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Antagonistas de Hormônios/síntese química , Benzimidazóis/farmacologia , Ácidos Carboxílicos/química , Técnicas de Química Combinatória , Diaminas/química , Antagonistas de Hormônios/farmacologia , Concentração Inibidora 50 , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-AtividadeRESUMO
The diphenylsulfonyl sulfonamide scaffold represented by 1 (WAY-316606) are small molecule inhibitors of the secreted protein sFRP-1, an endogenous antagonist of the secreted glycoprotein Wnt. Modulators of the Wnt pathway have been proposed as anabolic agents for the treatment of osteoporosis or other bone-related disorders. Details of the structure-activity relationships and biological activity from the first structural class of this scaffold will be discussed.
Assuntos
Piperidinas/química , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfanilamidas/síntese química , Sulfanilamidas/farmacologia , Proteínas Wnt/metabolismo , Animais , Linhagem Celular Tumoral , Genes Reporter/genética , Humanos , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular , Isomerismo , Camundongos , Estrutura Molecular , Ligação Proteica , Crânio/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfanilamidas/química , Proteínas Wnt/genéticaRESUMO
In this work, we describe an NMR-based method that utilizes an orientation media composed of the chiral polypeptide liquid crystal poly-gamma-benzyl-L-glutamate (PBLG) dissolved in CDCl(3), to measure the (1)H-(1)H, (1)H-(13)C and (13)C-(13)C residual dipolar couplings (RDCs) of (R) and (S)-ibuprofen. Calculated RDCs, obtained from the lowest energy conformers, are then compared with the experimentally measured RDCs to predict the stereochemistry of each enantiomer. Excellent agreement between calculated and experimental RDCs was found when the lowest energy structure of each enantiomer, obtained in a simulated PBLG/CDCl(3) environment, was used to back-calculate the RDCs. This method is generally useful for small molecular weight molecules that possess either one or two chiral centers, are soluble in low viscosity organic solvents, and will not crystallize (Clegg, Crystal Structure Analysis. Principles and Practice. New York: Oxford University Press; 2002) or cannot be derivatized with a Mosher's reagent (Dale and Mosher, J Am Chem Soc 1973;95:512-519).
Assuntos
Química Farmacêutica/métodos , Ibuprofeno/análise , Ibuprofeno/química , Espectroscopia de Ressonância Magnética/métodos , Tecnologia Farmacêutica/métodos , Química Orgânica/métodos , Cristalização , Modelos Químicos , Modelos Moleculares , Modelos Teóricos , Conformação Molecular , Estrutura Molecular , Solventes , EstereoisomerismoRESUMO
A high-resolution, phase-sensitive, natural abundance F2-coupled 1H-13C HSQC (F2HSQC) NMR experiment was developed to measure simultaneously both (n)D(HH) and 1D(CH) residual dipolar couplings (RDCs) of small molecules present in a chiral polypeptide liquid crystal solvent system composed of poly-gamma-benzyl-L-glutamate (PBLG) in CDCl3. Because this is an indirect-detection NMR experiment, the relatively small amount of sample (7.5 mg in this study) and short acquisition times (5 h) that are required make this HSQC experiment well suited for samples that are either limited in solubility or in quantity or require short analysis times. The F2HSQC experiment can be performed without any specialized equipment or sample modification and can enhance our ability to measure RDCs accurately and rapidly in polypeptide liquid crystal solvents.