Pieter B.M.W.M. Timmermans

Nonpeptide angiotensin II receptor antagonists

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.

BALANCED ANGIOTENSIN II RECEPTOR ANTAGONISTS. III: THE EFFECTS OF SUBSTITUTION AT THE IMIDAZOLE 5-POSITION

Abstract We wish to report on a series of substituted methyl esters and amides of DMP 811, which bind to both the AT 1 and AT 2 receptor subtypes. Some of the esters bind well to both receptor subtypes in the subnanomolar range when the optimal acid isostere is present together with an ortho-fluorine substituent on the biphenylmethyl group.

Balanced angiotensin II receptor antagonists. I. The effects of biphenyl “ortho”-substitution on AT1/AT2 affinities

Abstract Biphenyl “ortho”-substitution of DuP 753-like AT1-selective angiotensin II receptor antagonists provides AT2 affinity. When combined with a sulfonylcarbamate as the acid isostere, balanced AT1/AT2 receptor antagonists were obtained. Some compounds exhibited nanomolar affinities for both receptors and good AT2/AT1 ratios; these compounds also produce potent and prolonged antihypertensive effects in renal hypertensive rats.

Nonpeptide angiotensin II receptor antagonists : the discovery of DMP 581 and DMP 811

Abstract A novel series of 4-alkylimidazoles have been prepared. Two of these compounds, DMP 581, 4-ethyl-2-propyl- 1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidiazole-5-carboxaldehyde, and DMP 811, 4-ethyl-2-propyl-1-[[2′-(1H- tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylic acid, possess among the highest oral antihypertensive potencies yet described for an angiotensin II antagonist. In addition, prodrugs of DMP 811 have been developed to further enhance the oral bioavailability of the parent diacid.

Imidazolinones as nonpeptide angiotensin II receptor antagonists

Abstract A series of biphenyl imidazolinones were synthesized as nonpeptide angiotensin II receptor antagonists. While those compounds with a tetrazole functionality were found to be AT 1 selective, those with a sulfonamide moiety showed affinities for both the AT 1 and the AT 2 sites. Representative compounds were very active in lowering blood pressure in conscious renal hypertensive rats following intravenous administration.

Balanced angiotensin II receptor antagonists. II.1,2 4-aminomethyl- and acylaminomethylimidazoles

Abstract The introduction of aminomethyl and acylaminomethyl substituents at the imidazole 4-position of 1-biphenylmethylimidazole-5-carboxylates imparts affinity for the AT2 receptor. The highest affinity was found with the 4-(2-pyridyl)-piperazin-1-ylmethyl group and the use of hexanoylsulfonamide as a tetrazole replacement, which led to XM953 (18d), with an AT2IC50 of 20 nM and an AT2/AT1IC50 ratio of 3.

Cardiovascular new drug discovery of the future: Molecules, genes, and machines

Publisher Summary Cardiovascular disease refers to any disease which involves the heart (cardio) or the blood vessels (vascular). This chapter discusses current cardiovascular diseases and drug treatment, some new molecules in the pipeline, and the scientific and technological advances that may provide the novel drugs in the not too distant future. The effectiveness of pharmacological treatment in reducing the morbidity and mortality of cardiovascular disease is clearly established for antihypertensives and ACE inhibitors in heart failure and to more limited extent for cholesterol lowering agents. Hypertension and hyperlipidemia are risk factors for the potentially morbid events of stroke, myocardial infarction, heart failure, and renal failure. Drug discovery programs of the past–present have primarily focused on the clinical signs and endpoints rather than their cellular origins. Stroke is a leading cause of disability and death especially in the elderly. There is a complex sequence of events involving ischemia and reperfusion which activates neurotransmitter systems such as the induction of inflammation by oxygen-free radicals.