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1.
J Med Chem ; 35(5): 944-53, 1992 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-1548684

RESUMO

In a preliminary communication (J. Med. Chem. 1989, 32, 11-13) a series of perfluoro-N-[4-(1H-tetrazol-5ylmethyl)phenyl]alkana mides (perfluoro anilides I), designed as novel analogues of ciglitazone, were reported to possess oral antidiabetic activity in two genetic animal models of non-insulin-dependent diabetes mellitus (NIDDM): obese (ob/ob) and diabetic (db/db) mice. In this report, the results from a structure-activity relationship (SAR) study of the series I are described. Comprehensive statistical analysis among the 86 analogues screened for blood glucose lowering in ob/ob mice was achieved by a new application of a general statistical procedure which made it possible to make meaningful comparisons between more than 140 separate experiments (N = 2966). Perfluoro anilides I lowered plasma glucose in the hyperglycemic ob/ob and db/db mice but not in euglycemic normal rats. In the hyperinsulinemic ob/ob mouse, decreases in plasma insulin levels paralleled the decline in plasma glucose. Potency and efficacy in the series was shown to be dependent on the length of the perfluorocarbon chain (RF) of I. Optimal activity occurred with the C7 and C8 RF chains. The more extensive SAR studies reported here, indicated that the lipophilic RF chain is the most important structural element of I since neither the phenyl nor tetrazole rings present in anilides I were necessary for antihyperglycemic activity while medium length (C7-C8) RF chains, especially the C7F15 chain, were shown to confer antihyperglycemic activity in ob/ob mice to a wide variety of structures.


Assuntos
Fluorocarbonos/química , Fluorocarbonos/uso terapêutico , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Tiazolidinedionas , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Feminino , Insulina/sangue , Camundongos , Camundongos Obesos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/uso terapêutico
2.
J Med Chem ; 42(5): 819-32, 1999 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-10072680

RESUMO

As described in the preceding paper (Arvanitis et al. J. Med. Chem. 1999, 42), anilinopyrimidines I were identified as potent antagonists of corticotropin-releasing hormone-1 receptor (CRH1-R, also referred to as corticotropin-releasing factor, CRF1-R). Our next goal was to understand the receptor-bound conformation of the antagonists and to use this information to help guide preclinical optimization of the series and to develop new leads. Since receptor structural information was not available, we assumed that these small, high-affinity antagonists would tend to bind in conformations at or energetically close to their global minima and that rigid analogues that maintained the important stereoelectronic features of the bound anilinopyrimidine would also bind tightly. Conformational preferences and barriers to rotation of the anilinopyrimidines were determined by semiempirical methods, and X-ray and variable-temperature NMR spectroscopy provided experimental results that correlated well with calculated structures. Using these data, a key dihedral angle was constrained to design fused-ring analogues, substituted N-arylpyrrolopyridines II, synthesis of which provided CRH1 receptor antagonists with potency equal to that of the initial congeneric leads (Ki = 1 nM) and which closely matched the conformation held by the original compound, as determined by crystallography. In addition to providing a useful template for further analogue synthesis, the study unequivocally determined the active conformation of the anilinopyrimidines. Theoretical and spectroscopic studies, synthesis, and receptor binding data are presented.


Assuntos
Piridinas/síntese química , Pirimidinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Cristalografia por Raios X , Desenho de Fármacos , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Piridinas/química , Pirimidinas/química , Soluções , Relação Estrutura-Atividade
3.
J Med Chem ; 42(5): 805-18, 1999 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-10072679

RESUMO

Screening of our chemical library using a rat corticotropin-releasing hormone (CRH) receptor assay led to the discovery that 2-anilinopyrimidine 15-1 weakly displaced [125I]-0-Tyr-oCRH from rat frontal cortex homogenates when compared to the known peptide antagonist alpha-helical CRH(9-41) (Ki = 5700 nM vs 1 nM). Furthermore, 15-1 weakly inhibited CRH-stimulated adenylate cyclase activity in the same tissue, but it was less potent than alpha-helical CRH(9-41) (IC50 = 20 000 nM vs 250 nM). Systematic structure-activity relationship studies, using the cloned human CRH1 receptor assay, defined the pharmacophore for optimal binding to hCRH1 receptors. Several high-affinity 2-anilinopyrimidines and -triazines were discovered, some of which had superior pharmacokinetic profiles in the rat. This paper describes the structure-activity studies which improved hCRH1 receptor binding affinity and pharmacokinetic parameters in the rat. Compound 28-17 (mean hCRH1 Ki = 32 nM) had a significantly improved pharmacokinetic profile in the rat (19% oral bioavailability at 30 mg/kg) as well as in the dog (20% oral bioavailability at 5 mg/kg) relative to the early lead structures.


Assuntos
Pirimidinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Triazinas/síntese química , Animais , Disponibilidade Biológica , Cães , Lobo Frontal/metabolismo , Humanos , Técnicas In Vitro , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacocinética , Triazinas/farmacologia
4.
J Med Chem ; 42(5): 833-48, 1999 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-10072681

RESUMO

The synthesis and CRF receptor binding affinities of several new series of N-aryltriazolo- and -imidazopyrimidines and -pyridines are described. These cyclized systems were prepared from appropriately substituted diaminopyrimidines or -pyridines by nitrous acid, orthoester, or acyl halide treatment. Variations of amino (ether) pendants and aromatic substituents have defined the structure-activity relationships of these series and resulted in the identification of a variety of high-affinity agents (Ki's < 10 nM). On the basis of this property and lipophilicity differences, six of these compounds (4d,i,n,x, 8k, 9a) were initially chosen for rat pharmacokinetic (PK) studies. Good oral bioavailability, high plasma levels, and duration of four of these compounds (4d,i,n,x) prompted further PK studies in the dog following both iv and oral routes of administration. Results from this work indicated 4i,x had properties we believe necessary for a potential therapeutic agent, and 4i1 has been selected for further pharmacological studies that will be reported in due course.


Assuntos
Piridinas/metabolismo , Piridinas/farmacocinética , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular , Cães , Humanos , Camundongos , Piridinas/síntese química , Piridinas/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
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