RESUMEN
A series of peptide mimetic aldehyde inhibitors of calpain I was prepared in which the P(2) and P(3) amino acids were replaced by substituted 3,4-dihydro-1,2-benzothiazine-3-carboxylate 1,1-dioxides. The effect of 2, 6, and 7-benzothiazine substituents and the P(1) amino acid was examined. Potency of these inhibitors, 15c-p, against human recombinant calpain I is particularly dependent upon the 2-substituent, with methyl and ethyl generally more potent than hydrogen, isopropyl, isobutyl, or benzyl. The more potent diastereomer of 15m possesses the (S) absolute configuration at the 3-position of the 3,4-dihydro-1,2-benzothiazine. Potency of the best inhibitors in this series (IC(50) = 5-7 nM) compares favorably with that of conventional N-benzyloxycarbonyl dipeptide aldehyde inhibitors bearing L-Leu or L-Val residues at P(2). The achiral unsaturated 1,2-benzothiazine analogues 26a-d are also potent calpain I inhibitors, while 3,4-dihydro-2,1-benzoxathiin (15a,b), 1,2,4-benzothiadiazine (32a,b), and tetrahydroisoquinolinone (36a,b) analogues are less potent.
Asunto(s)
Aldehídos/síntesis química , Calpaína/química , Óxidos S-Cíclicos/síntesis química , Péptidos/química , Fenilalanina/síntesis química , Inhibidores de Proteasas/síntesis química , Tiazinas/síntesis química , Aldehídos/química , Aldehídos/farmacología , Calpaína/metabolismo , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacología , Electroforesis en Gel de Poliacrilamida , Humanos , Modelos Moleculares , Imitación Molecular , Fenilalanina/análogos & derivados , Fenilalanina/química , Fenilalanina/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad , Tiazinas/química , Tiazinas/farmacología , Células Tumorales CultivadasRESUMEN
Dipeptidyl phosphorus compounds were synthesized as potential bioisosteric mimics of peptide alpha-ketoesters and alpha-ketoacids. alpha-Ketophosphonate Cbz-Leu-Leu-P(O)(OCH3)2 (1b), containing an alpha-ketoester bioisostere, inhibits human calpain I with an IC50 = 0.43 microM. The potency of 1b compares very favorably with that of alpha-ketoester Cbz-Leu-Leu-CO2Et (IC50 = 0.60 microM). Monomethyl ketophosphonate Cbz-Leu-Leu-P(O)(OH)(OCH3) (1a, IC50 = 5.2 microM), an alpha-ketoacid mimic, is less potent. Dibutyl and dibenzyl alpha-ketophosphonates 1c,e,f are much less potent calpain inhibitors than dimethyl alpha-ketophosphonate 1b. alpha-Ketophosphinate 1g (IC50 = 0.37 microM) and alpha-ketophosphine oxide 1h (IC50 = 0.35 microM) are also potent calpain inhibitors.
Asunto(s)
Calpaína/antagonistas & inhibidores , Dipéptidos , Organofosfonatos , Óxidos , Fosfinas , Ácidos Fosfínicos , Dipéptidos/síntesis química , Dipéptidos/química , Dipéptidos/farmacología , Humanos , Organofosfonatos/síntesis química , Organofosfonatos/química , Organofosfonatos/farmacología , Óxidos/síntesis química , Óxidos/química , Óxidos/farmacología , Fosfinas/síntesis química , Fosfinas/química , Fosfinas/farmacología , Ácidos Fosfínicos/síntesis química , Ácidos Fosfínicos/química , Ácidos Fosfínicos/farmacología , Proteínas Recombinantes/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
The renin-angiotensin system (RAS) has been demonstrated to be a key element in blood pressure regulation and fluid volume homeostasis. Since angiotensin II (AII) is the effector molecule of the RAS, the most direct approach to block this system is to antagonize AII at the level of its receptor. Therefore, at Du Pont Merck the working hypothesis has been that the identification of metabolically stable and orally effective AII-receptor antagonists would constitute a new and superior class of agents useful in treating hypertension and congestive heart failure. Our program began with a detailed pharmacologic evaluation of some simple N-benzylimidazoles, originally described by Takeda Chemical Industries in Osaka, Japan. They were found to be a series of weak but selective AII-receptor antagonists with a competitive mode of action. We embarked on a program aimed to design and synthesize more potent and orally effective nonpeptide antagonists, while attempting to preserve their selective affinity for the AII receptor. The first major breakthrough in our efforts to increase the potency of these compounds came with the development of a series of N-benzylimidazole phthalamic acid derivatives. Although effective at lowering blood pressure when administered intravenously, the phthalamic acids were devoid of oral activity. The first orally active AII antagonists came with the discovery of the biphenyl carboxylic acids. Although these compounds are absorbed after oral dosing, their bioavailability was less than desired. In the hope of improving the oral absorption of these biphenyls, we investigated a variety of acidic groups as bioisosteric replacements for the carboxylic acid. The key to the discovery of nonpeptide AII-receptor antagonists with improved oral activity and duration of action resulted from replacing the carboxylic acid group with the isosteric but more lipophilic tetrazole ring. Hence, our efforts culminated in the discovery of losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]imidazole, potassium salt), a highly potent angiotensin type 1 (AT1) selective receptor antagonist with a long duration of action. Losartan is currently undergoing clinical investigation for the treatment of hypertension. The history, including the rationale for the design of the compounds, and ensuing structure-activity relationships of losartan and related analogs will be described. Many of the newer compounds exceed the potency of losartan, and the best compounds in the series rival the affinity of the endogenous ligand, AII, for its receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Antagonistas de Receptores de Angiotensina , Angiotensina II/antagonistas & inhibidores , Antihipertensivos/uso terapéutico , Compuestos de Bifenilo/química , Compuestos de Bifenilo/uso terapéutico , Diseño de Fármacos , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Imidazoles/química , Imidazoles/uso terapéutico , Losartán , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Tetrazoles/química , Tetrazoles/uso terapéuticoRESUMEN
Some simple N-benzylimidazoles, originally described by Takeda Chemical Industries (Osaka, Japan), were characterized to be very weak but selective nonpeptide angiotensin II (Ang II) receptor antagonists with a competitive mode of action. Chemical modifications of these led to EXP6155 and EXP6803, which showed approximately 10- and 100-fold higher affinity, respectively, but were orally ineffective. Oral activity was obtained for the biphenyl carboxylic acid derivatives EXP7711 and especially EXP9654. A further advance in the design of nonpeptide Ang II receptor antagonists was provided by DuP 753, an analogue of EXP7711 in which the carboxylic acid function is replaced by its tetrazol-5-yl equivalent. DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bi phe nyl-4- yl)methyl]imidazole, potassium salt) displaces radiolabeled Ang II from its specific binding sites in various tissues, affording IC50 values of approximately 20 nM. DuP 753 competitively antagonizes Ang II-induced responses in various in vitro and in vivo preparations but does not influence those to KCl, norepinephrine, vasopressin, and others, nor does it affect converting enzyme and renin. In high renin animal models of elevated arterial blood pressure, intravenous and oral administrations of DuP 753 produce a sustained decrease in pressure without influencing heart rate. Marked antihypertensive effects are observed in spontaneously hypertensive rats, but no efficacy is noticed in deoxycorticosterone acetate hypertensive animals. DuP 753 showed no agonistic properties in any of the above test systems and has been chosen to undergo clinical trials for the treatment of hypertension. In rats, the 5-carboxylic acid (EXP3174) represents a major metabolite of DuP 753.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Angiotensina II/metabolismo , Antihipertensivos/farmacología , Compuestos de Bifenilo/farmacología , Imidazoles/farmacología , Receptores de Angiotensina/efectos de los fármacos , Tetrazoles/farmacología , Animales , Compuestos de Bifenilo/metabolismo , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/metabolismo , Losartán , Tetrazoles/metabolismoRESUMEN
A new series of nonpeptide angiotensin II (AII) receptor antagonists has been prepared. These N-(biphenylyl-methyl)imidazoles, e.g. 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5- (hydroxymethyl)imidazole, differ from the previously reported N-(benzamidobenzyl)imidazoles and related compounds in that they produce a potent antihypertensive effect upon oral administration; the earlier series generally were active only when administered intravenously. It has been found that the acidic group at the 2'-position of the biphenyl is essential. Only ortho-substituted acids possess both high affinity for the AII receptor and good oral antihypertensive potency. The carboxylic acid group has been replaced with a variety of acidic isosteres, and the tetrazole ring has been found to be the most effective. The tetrazole derivative, DuP 753, is currently in development for the treatment of hypertension.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Antihipertensivos/síntesis química , Compuestos de Bifenilo/síntesis química , Imidazoles/síntesis química , Administración Oral , Glándulas Suprarrenales/metabolismo , Animales , Antihipertensivos/uso terapéutico , Compuestos de Bifenilo/metabolismo , Compuestos de Bifenilo/uso terapéutico , Fenómenos Químicos , Química , Hipertensión/tratamiento farmacológico , Imidazoles/metabolismo , Imidazoles/uso terapéutico , Losartán , Masculino , Estructura Molecular , Ratas , Ratas Endogámicas , Receptores de Angiotensina/metabolismo , Relación Estructura-Actividad , Tetrazoles/síntesis química , Tetrazoles/uso terapéuticoRESUMEN
Since angiotensin II (AII) is the effector molecule of the renin angiotensin system, the most direct approach to interfere with this system would be to antagonize AII at the level of its receptor. AII receptor antagonists would represent an ideal species, for regardless of how and where AII is produced, its function could be specifically turned off. However, the AII receptor antagonists currently available have been limited to AII-like peptides and their usefulness as therapeutics and pharmacologic tools has been hampered by their lack of oral bioavailability, metabolic instability, and partial agonistic activity. A detailed pharmacologic characterization of some simple N-benzylimidazoles, originally described by Takeda Chemical Industries (Osaka, Japan), identified this class of compound as very weak but selective AII receptor antagonists with a competitive mode of action. Encouraged by the quality of these lead compounds, we embarked on a synthetic program aimed at designing more potent and orally effective antagonists, while preserving their selectivity for the AII receptor. Our efforts have culminated in the discovery of DuP 753, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)biph eny l-4-yl) methyl]imidazole, potassium salt, a potent, nonpeptide AII receptor antagonist.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Antihipertensivos , Animales , Imidazoles/farmacología , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Although the most direct way to interfere with the renin-angiotensin system (RAS) is at the level of the angiotensin II (AII) receptor, the currently available AII receptor antagonists are peptides still retaining significant agonistic properties with the obvious drawbacks of limited stability and lack of oral activity. We have characterized simple N-benzylimidazoles as weak, but selective AII receptor antagonists with a competitive mode of action. Chemical modification of these early leads led to EXP6155 and EXP6803, which show approximately 10- and 100-fold higher affinity. Oral activity was obtained for EXP7711, and in particular for EXP9654. This class of compounds displaces 3H-AII from its specific binding sites in various tissues. They competitively antagonize AII-induced responses in various in vitro and in vivo preparations, but do not influence AII-induced responses to KCl, norepinephrine, and vasopressin, nor do they affect converting enzyme or renin. In high renin models of elevated blood pressure, such as the renal hypertensive rat and sodium-depleted dog, these substances produce a sustained decrease in arterial pressure without changing heart rate after intravenous and oral (EXP7711 and EXP9654) administration. None of these compounds showed agonistic activity in any of the above test systems. In conclusion, the nonpeptide structures described herein are selective and competitive AII receptor antagonists and add another dimension to the arsenal of drugs manipulating the RAS.
Asunto(s)
Angiotensina II , Antagonistas de Receptores de Angiotensina , Compuestos de Bifenilo/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Unión Competitiva , Compuestos de Bifenilo/metabolismo , Fenómenos Químicos , Química , Humanos , Hipertensión Renovascular/tratamiento farmacológico , Imidazoles/metabolismo , Obstrucción de la Arteria Renal/complicacionesRESUMEN
A new class of potent antihypertensives has been discovered that exert their effect through blockade of the angiotensin II (AII) receptor. Most AII antagonists reported so far are peptide mimics of the endogenous vasoconstrictor octapeptide angiotensin II. The compounds of this paper are nonpeptides and therefore constitute a new class of potent AII receptor antagonists. Based on the overlap of a conformation of AII with literature lead 3, a hypothesis was developed suggesting the need for an additional acidic functionality to increase the lead's potency. The substitution of an additional carboxylic acid resulted in a 10-fold increase in binding affinity observed for diacid 4. The binding affinities for subsequent compounds were eventually increased 1000-fold over that of the literature leads through a systematic SAR study. Thus the AII receptor binding affinity [IC50 (microM)] of 15 microM for literature lead 1, for example, was increased to 0.018 and 0.012 microM for compounds 33 and 53. A structure-affinity relationship has been found requiring the presence of four key elements for good activity: (1) an additional phenyl ring at the N-benzyl para position of the benzylimidazole nucleus, (2) an acidic functionality at the ortho position of the terminal aromatic ring, (3) a lipophilic side chain at the imidazole 2-position of three to five carbon atoms in length, and (4) a group at the imidazole 5-position capable of hydrogen bonding. The synthesis as well as the pharmacological activity of the compounds in this new series of AII receptor antagonists are presented.
Asunto(s)
Angiotensina II/antagonistas & inhibidores , Antihipertensivos/síntesis química , Imidazoles/síntesis química , Receptores de Angiotensina/efectos de los fármacos , Antagonistas de Receptores de Angiotensina , Animales , Sitios de Unión , Presión Sanguínea/efectos de los fármacos , Fenómenos Químicos , Química , Cristalografía , Imidazoles/metabolismo , Imidazoles/farmacología , Masculino , Modelos Moleculares , Ratas , Ratas Endogámicas , Receptores de Angiotensina/metabolismo , Relación Estructura-ActividadRESUMEN
The most direct approach to block the function of the renin-angiotensin system would be to antagonize angiotensin II (AII) at the level of its receptor. However, the AII receptor antagonists currently available, such as saralasin, are peptides which still retain agonistic activity and lack oral bioavailability. We have identified the N-benzylimidazoles, S-8307 and S-8308, as weak, but selective nonpeptide AII receptor antagonists. These initial leads were subsequently converted into more potent compounds, such as EXP6155, EXP6803 and EXP7711, while maintaining the selectivity. The compounds displace 3H-AII from its specific binding sites in adrenal cortical membranes and smooth muscle cells. They competitively inhibit the vasoconstrictor response to AII in various in vivo and in vitro preparations, but do not influence those to KCl, norepinephrine, and vasopressin. Converting enzyme and renin are not affected by these agents. In renal hypertensive rats and sodium-depleted dogs our compounds cause a sustained decrease in arterial pressure following intravenous and oral (EXP7711) administration, and are devoid of agonistic properties. Taken together, these nonpeptide structures are true competitive AII receptor antagonists and represent a new class of effective antihypertensive agents.