RESUMO
A combinatorial approach for rapid optimization of a vitronectin receptor (alphavbeta3) inhibitor lead was accomplished by solid-phase synthesis. Orthogonally bis protected 2,3-diaminopropionic acid was used to immobilize the C-terminus of the molecule. Selective deprotection and functionalization of the alpha-amino group followed by acyl resorcinol scaffold attachment and N-terminus diversification was used to explore structure activity relationship (SAR).
Assuntos
Receptores de Vitronectina/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
A series of xanthine sulfonamides is presented as a class of calcitonin (CT) inducers - a potentially new method for treating diseases associated with postmenopausal bone loss such as osteoporosis. We have found that certain di-n-butylxanthine sulfonamides 4 upregulate CT transcription in a CT-luciferase reporter gene assay (CT-luci) and increase the production and release of CT in a CT secretion/RIA assay (CTS). In addition, these compounds do not have potent PDE4 inhibitory activity as do the related xanthine methylene ketones such as denbufyllene (2). One compound in particular (9) shows a transcription activation ratio (TAR) of 2.1 in CT-luci, a CTS increase of 3.6-fold, and a PDE4 (phosphodiesterase type IV) IC(50) = 4.1 microM. In addition, this compound showed a statistically significant 47% trabecular bone protection in ovariectomized-induced osteopenia (OVX) rats as determined by assay when administered for 4 weeks at 30 mg/kg/day, i. p. by quantitative computed tomography (QCT). When administered p.o., compound 9 shows 50% trabecular bone protection when administered for 3 weeks at 50 mg/kg/day, i.p. This compared with salmon CT which shows 62% trabecular bone protection when administered at 50 IU/kg/day for 4 weeks.
Assuntos
Calcitonina/biossíntese , Sulfonamidas/síntese química , Xantinas/síntese química , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Animais , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/patologia , Calcitonina/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , Genes Reporter , Humanos , Luciferases/genética , Ovariectomia , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Transcrição Gênica , Xantinas/química , Xantinas/farmacologiaRESUMO
Solid-phase synthesis is a valuable tool for drug discovery research. The value is particularly evident in lead optimization work where it contributes to the rapid and thorough identification of the optimal drug candidate within a lead series. Solid-phase synthesis methods continue to be developed at a rapid pace, and these methods will eventually become standard tools for medicinal chemists. This review is focused on papers published since the beginning of 1998, which describe the use of solid-phase synthesis in lead optimization.
RESUMO
Described in this paper is the synthesis and pharmacological activity of five metabolites of the angiotensin II antagonist tasosartan (1). Of particular interest is the effect of the additional acidic group of the enol metabolite (8) on activity. As suggested by the structural-activity relationship of other angiotensin II antagonist series, a second acidic group can improve receptor binding activity but decrease in vivo activity after oral dosing. The metabolic introduction of a second acidic group in tasosartan bypasses this problem and contributes to the excellent profile of the compound. A molecular modeling study provides a rationale for the role of the enol group of 8 in AT1 receptor binding.
Assuntos
Angiotensina II/antagonistas & inibidores , Modelos Moleculares , Piridonas/síntese química , Pirimidinas/síntese química , Pirimidinas/metabolismo , Tetrazóis/metabolismo , Administração Oral , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Bloqueadores do Receptor Tipo 2 de Angiotensina II , Antagonistas de Receptores de Angiotensina , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Técnicas In Vitro , Injeções Intravenosas , Fígado/efeitos dos fármacos , Fígado/metabolismo , Conformação Molecular , Piridonas/administração & dosagem , Piridonas/química , Piridonas/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Receptores de Angiotensina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of pyrido[2,3-d]pyrimidine angiotensin II (A II) antagonists was synthesized and tested for antagonism of A II. Compounds with a biphenylyltetrazole pharmacophore and small alkyl groups at the 2- and 4-positions of the pyridopyrimidine ring were found to be the most potent in an AT1 receptor binding assay and in blocking the A II pressor response in anesthetized, ganglion-blocked A II-infused rats. 5,8-Dihydro-2,4-dimethyl-8-[(2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl)methyl]pyrido[2,3-d]pyrimidin-7(6H)-one (4a) was one of the more potent compounds in the binding assay and was the most efficacious compound in the A II-infused rat model. Further study of 4a in Goldblatt (2K-1C) rats showed the compound to have oral bioavailability and to be an efficacious and potent compound in a high renin form of hypertension.
Assuntos
Piridinas/síntese química , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Tetrazóis/síntese química , Tetrazóis/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Pressorreceptores/efeitos dos fármacos , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tetrazóis/farmacocinéticaRESUMO
A series of naphthalenyl 3H-1,2,3,5-oxathiadiazole 2-oxides was prepared and tested for antihyperglycemic activity in the db/db mouse, a model for type 2 (non-insulin dependent) diabetes mellitus. Substitution at the 1-, 5-, or 8-positions of the naphthalene ring with a halogen was found to be beneficial to antihyperglycemic activity. 4-[(5-Chloronaphthalen-2-yl)methyl]-3H-1,2,3,5-oxathiadiazole++ + 2-oxide (45), one of the most potent compounds in this series, was selected for further pharmacological evaluation.
Assuntos
Hipoglicemiantes/síntese química , Naftalenos/síntese química , Tiadiazóis/síntese química , Animais , Glicemia/efeitos dos fármacos , Feminino , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Obesos , Naftalenos/química , Naftalenos/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacologiaRESUMO
The synthesis and Class III antiarrhythmic activity of a series of 4-[(methylsulfonyl)amino]benzamides and sulfonamides are described. Selected compounds show a potent Class III activity and are devoid of effects on conduction both in vitro (dog Purkinje fibers) and in vivo (anesthetized dogs). Compounds having a 2-aminobenzimidazole group were found to be the most potent, and one compound having this heterocycle (5, WAY-123,398) was selected for further characterization. Compound 5 was shown to have good oral bioavailability and a favorable hemodynamic profile to produce a 3-fold increase of the ventricular fibrillation threshold and to terminate ventricular fibrillation, restoring sinus rhythm in anesthetized dogs. Voltage-clamp studies in isolated myocytes show that 5 is a potent and specific blocker of the delayed rectifier potassium current (IK) at concentrations that cause significant prolongation of action potential duration.