ABSTRACT
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.
Subject(s)
Pyrimidines/chemical synthesis , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Triazines/chemical synthesis , Animals , Biological Availability , Dogs , Frontal Lobe/metabolism , Humans , In Vitro Techniques , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism , Recombinant Proteins/metabolism , Structure-Activity Relationship , Triazines/chemistry , Triazines/pharmacokinetics , Triazines/pharmacologyABSTRACT
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.
Subject(s)
Pyridines/metabolism , Pyridines/pharmacokinetics , Pyrimidines/metabolism , Pyrimidines/pharmacokinetics , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Cell Line , Dogs , Humans , Mice , Pyridines/chemical synthesis , Pyridines/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
Acyl-CoA:cholesterol acyltransferase (ACAT) is the enzyme largely responsible for intracellular cholesterol esterification. A systemic inhibitor of ACAT is believed to be able to slow or even reverse the atherosclerotic process. Towards that goal, a series of cyclic sulfides, derived from the hetero-Diels-Alder reaction of thioaldehydes with 1,3-dienes, and bearing carboxamide substituents, were prepared and evaluated for in vitro (in several tissues and species) and ex vivo ACAT inhibition. Minor changes in subsequent structure were found to have a significant effect in optimization of the biological activity of this series of compounds.
Subject(s)
Aldehydes/chemistry , Enzyme Inhibitors/chemistry , Sterol O-Acyltransferase/antagonists & inhibitors , Sulfhydryl Compounds/chemistry , Animals , Chemical Phenomena , Chemistry , Chromatography, High Pressure Liquid , Male , Microsomes, Liver/enzymology , Rats , Rats, Sprague-DawleyABSTRACT
Acyl-CoA:cholesterol acyltransferase (ACAT) is the primary enzyme involved in intracellular cholesterol esterification. Arterial wall infiltration by macrophages and subsequent uncontrolled esterification of cholesterol leading to foam cell formation is believed to be an important process which leads to the development of fatty streaks. Inhibitors of the ACAT enzyme may retard this atherogenic process. We have recently discovered a series of imidazoles which are potent in vitro ACAT inhibitors in the J774 macrophage cell culture assay. This paper will describe the design, synthesis, and structure--activity relationship for this very potent series of compounds.
Subject(s)
Macrophages/enzymology , Sterol O-Acyltransferase/antagonists & inhibitors , Animals , Cell Line , Drug Design , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Isoenzymes/antagonists & inhibitors , Mice , Microsomes, Liver/enzymology , Rats , Structure-Activity RelationshipABSTRACT
A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been synthesized and demonstrated to be potent inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). The design, synthesis, and structure-activity relationships for this series are reported herein. One of the compounds from this series, N'-(2,4-difluorophenyl)-N-[5-[(4,5-diaryl-1H-imidazol-2- yl)thio]pentyl]-N-heptylurea (DuP 128), was selected for development as an intestinally active ACAT inhibitor. DuP 128 is a potent ACAT inhibitor in vitro and in vivo, inhibiting ACAT in rat hepatic microsomes with an IC50 = 10 nM and possessing potent antihypercholesterolemic activity in vivo.