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.

A series of novel cyclic peptides related to DMP 757 bearing heterocyclic and otherwise modified linking moieties were prepared by solution-phase methods. Synthetic methods for the preparation of linking groups and cyclic peptides are presented. In vitro data for the purpose of QSAR is discussed.

A series of novel conjugated aromatic 4-amino- and 4-amido-piperidines which are potent sigma receptor ligands are described. These ligands exhibited good to excellent selectivities for binding at sigma versus D2 and 5-HT2 receptors.

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A series of novel cinnamyl and propargyl ether derivatives of alkyl piperidines which show high affinity for sigma and 5HT2 receptors are described. The ligands exhibit high selectivities for these receptors over D2 as well as good activity in vivo in anti-mescaline scratch assay.

A series of (perfluoroalkyl)imidazoles have been prepared and are potent angiotensin II antagonists. One of these compounds, DuP 532, 4-pentafluoroethyl-2-propyl-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylic acid, is a selective antagonist of angiotensin II which causes a marked and long-lasting drop in blood pressure when administered orally to a renal hypertensive rat.

A series of lipophilic Nα-amido-neurotensin(9–13) analogs was prepared. These acylated pentapeptides exhibited good neurotensin receptor binding, as well as in vivo analgesic activity via i.c.v. and even intravenous routes of administration.

The neurotensin C-terminal pentapeptide has been systematically simplified to identify a minimal fragment with in vivo analgesic activity and neurotensin receptor binding ability. Di-, tri-, and tetrapeptide fragments were inactive. Pentapeptide simplifications established that only the arginine could be replaced with simpler amino acids and retain activity in each assay.

A series of amide bond modified neurotensin c-terminal pentapeptides has been prepared and tested for their in vivo analgesic properties. Reduced amide function and trans double bond isosteres did show analgesic activity.

2-Amino-1,4-dihydro-4-(2-[-4[4-(2-methoxyphenyl)-1-piperazinyl]- butylsulfinyl]phenyl)-6-methyl-5-nitro-3-pyridine carboxylic acid methyl ester (XB513) was designed to combine the calcium agonistic and alpha-1 adrenergic receptor antagonistic properties in the same molecule. It inhibited the specific binding of [3H] nitrendipine in rat cardiac ventricular membranes with an IC50 of 1.2 microM, which is 20-fold greater than the standard calcium agonist Bay K 8644. It displaced [3H]prazosin in rat brain membranes with an IC50 of 29 nM. XB513 caused concentration-dependent positive inotropic responses in isolated electrically paced guinea pig left atria with an EC50 of 1.2 microM and was 10 times less potent than Bay K 8644. In rabbit aorta, XB513 inhibited the contractile effect of 16 nM norepinephrine with an IC50 of 89 nM. In an acute heart failure dog model produced by an overdose of propranolol, XB513 at 0.3 to 3 mg/kg i.v. dose-dependently reversed the decreased mean arterial pressure, cardiac output and dP/dt as well as the increased left ventricular end diastolic pressure induced by propranolol. In conscious instrumented dogs, XB513 at 0.1 and 0.3 mg/kg i.v. increased dP/dt and heart rate significantly, with a minor effect on mean arterial pressure. In summary, this study demonstrates that XB513 is a novel chemical entity possessing both calcium agonistic and alpha-1 adrenergic receptor blocking properties and thus may represent a new class of agents for the treatment of congestive heart failure.

A number of analogs of the cognition enhancing agent DuP 996 were prepared by varying the core structure and pendant groups in an independent fashion. The SAR of 2-, 3-, and 4-pyridinylmethyl groups as pendant groups on selected cores was examined.

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.Over the past 2 years, most of the major pharmaceutical companies have instituted substantial programs targeted at AII-receptor antagonists. The structural features of the compounds currently undergoing clinical evaluation will also be briefly reviewed.

The results of a detailed study of the structure-activity relationships in the series of compounds represented by DuP 747 are described.