Winston S. Marshall

Angiotensin ii antagonists

Acute blockade of the renin-angiotensin system with the parenterally active angiotensin II antagonist saralasin has been shown to effectively lower blood pressure in a large fraction of patients with essential hypertension and to improve hemodynamics in some patients with congestive heart failure. It is now possible to antagonize chronically angiotensin II at its receptor using the non-peptide angiotensin II inhibitor losartan (DuP 753, MK 954). When administered by mouth, this compound induces a dose-dependent inhibition of the pressor response to exogenous angiotensin II. This effect is closely related to circulating levels of the active metabolite E3174. Preliminary studies performed in hypertensive patients suggest that losartan has a blood pressure lowering action equivalent to that of an ACE inhibitor. Whether this compound will compare favorably with ACE inhibitors requires however further investigation.

Synthesis and structure-activity relationships of benzophenones as inhibitors of cathepsin D

Abstract Non peptide inhibitors of cathepsin D, an aspartyl protease that has been implicated in many disease states including Alzheimers disease, were prepared and evaluated. The most potent inhibitor of cathepsin D in this series was found to be (Z)-5-[[4-(4-benzoyl-3-hydroxy-2-propylphenoxy) methylphenyl]methylene]-2-thioxo-4-thiazolidinone ( 3f , IC 50 = 210 nM).

A Brief Review of Preclinical and Clinical Studies with LY171883 and Some Comments on Newer Cysteinyl Leukotriene Receptor Antagonists

Leukotriene receptor antagonists represent a new class of drugs that could potentially treat certain sequelae of asthma, septic shock, the adult respiratory distress syndrome, psoriasis, and various other human disorders.’-’ None have advanced far enough to be used as therapeutic agents. However, a few are in early clinical trials and one, LY171883, is currently in phase I1 evaluation. Use of LY171883 has generated some interesting observations that suggest a role for leukotrienes in human asthma.’ The four major leukotrienes-LTB,, LTC,, LTD4, and LTE,-exert their pharmacologic effects through specific receptors located on target organ~.’~’’ The major emphasis of our laboratory has been to develop agents that are capable of selectively interacting with leukotriene receptor sites, but that are unable to activate them as would the natural agonists. Such novel chemicals should function as pharmacologic antagonists and should have a mechanism of action similar to that of an antihistamine on a histaminergic receptor or an anticholinergic on a cholinergic receptor. Selective pharmacologic antagonists have been developed for LTD, and LTE, (see below), which are two of the cysteinyl-containing leukotrienes, but not for LTC4, which is the other leukotriene in this group and the third component of slow-reacting substance of anaphylaxis (SRS-A). Two reports have appeared in the literature describing agents that antagonize responses elicited by LTB4.”*12 Most of the newly described antagonists reduce responses to both LTD, and LTE,, thus suggesting a similarity in their receptors. LTC, receptors appear to differ from those for LTD, and LTE, in guinea pig ileum and trachea, where most studies have been carried o~t . ’ . ’~.’~ Recent observations by Buckner et a1.’59’6 have raised the possibility that, a t least in intralobar human airways, a single receptor might be responsive to all three cysteinyl leukotrienes. The present communication will review briefly the current experimental and clinical status of LY171883 and will also discuss newer leukotriene antagonists that hold promise as therapeutic agents.

Lowering of rat brain 3‐methoxy‐4‐hydroxyphenylethylene glycol sulphate (MOPEG sulphate) concentration by 2,6‐dichlorobenzylidene aminoguanidine

Baum, Shropshire & others (1970) have shown that 2,6-dichlorobenzylidene aminoguanidine (1) lowers blood pressure in experimental animals, and Bolme, Corrodi & Fuxe (1973) presented evidence that the mechanism might involve stimulation of central noradrenergic receptors. Generally, stimulants of neurotransmitter receptors in brain decrease the turnover and release of the neurotransmitter. Bolme & others (1973) showed that 2,6-dichlorobenzylidene aminoguanidine slowed the decline in noradrenaline after its synthesis was inhibited, suggesting noradrenaline turnover was decreased. Steady state concentration of 3-methoxy-4hydroxyphenylethylene glycol sulphate (MOPEG sulphate) has been suggested to be an index of noradrenaline turnover in rat brain (Meek & Neff, 1973).

Chiral recognition of the angiotensin II (AT1) receptor by a highly potent phenoxyproline octanoamide

Abstract The synthesis and in vitro biological evaluation of a novel series of diastereomeric phenoxyproline octanoamides ( 3–h ) as angiotensin II (AT 1 ) receptor antagonists are reported.

Structure-activity relationships (SAR) of the 3-alkyl substituents among a series of hydroxyacetophenone leukotriene antagonists

LY171883 is an orally active antagonist of leukotriene (LT) D4 and LTE4. A series of related compounds varying the position and nature of the alkyl side chain were synthesized and evaluated for their ability to block LTD4-induced contraction of guinea pig ileum. Maximal activity was obtained with n-propyl, n-butyl, and n-pentyl substituents with slightly reduced activity for longer side chains. Polar groups on the side chain substantially reduced activity. Thus, it appears that the leukotriene receptor site requires a nonpolar alkyl group of moderate size at the 3-position on this type of receptor antagonist.

Leukotriene (LT) receptor antagonists. Heterocycle-linked tetrazoles and carboxylic acids. LY203647

LY171883, 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl] ethanone, is an orally active antagonist of LTD4- and LTE4-induced responses in a variety of test systems. We prepared a new series of LT antagonists based on a proposed model of LY171883 binding to the LTE4 receptor in which then-propyl and tetrazole moieties of LY171883 occupy those parts of the receptor to which the C1-C5 chain and the cysteinyl carboxyl of LTE4 bind, respectively. The new compounds have an acidic function corresponding to the glycine carboxyl of LTD4 linked through a heterocyclic group which is proposed to bind to the LTD4 receptor where the cysteinyl glycine amide bond of LTD4 binds. LY203647, 1-[2-hydroxy-3-propyl-4-[4-[2-[4-(1H-tetrazol-5-yl) butyl]-2H-tetrazol-5-yl]butoxy]phenyl] ethanone, showed good LTD4 antagonist activity with a suitable pharmacologic and toxicologic profile and has been chosen for clinical evaluation.

Leukotriene Receptor Antagonism and Augmentation of β‐Receptor‐mediated Events by LY1718831

Abstract— LY171883, (1‐[2‐hydroxy‐3‐propyl‐4‐((4(1H‐tetrazol‐5‐yl)butoxy)phenyl]ethanone), a leukotriene (LT) D4/E4 receptor antagonist, was assessed in comparison with two well known phosphodiesterase inhibitors, isobutylmethyl‐xanthine (IBMX) and theophylline, for its ability to augment β‐receptormediated responses. Relaxation of carbachol‐contracted guinea‐pig trachea by isoprenaline was enhanced by the three agents in a dose‐dependent manner. A two‐fold enhancement of isoprenaline‐induced smooth muscle relaxation was produced by 2.5 μM IBMX, 28 μM LY171883, or 140 μM theophylline. Similar concentrations of IBMX or theophylline did not antagonize LTE4‐induced tracheal contractions; LY171883 totally inhibited the response and had significant LTE4 receptor antagonist activity even at 10‐fold lower concentrations. Antigen‐induced release of histamine and LTC4 from guinea‐pig lung was reduced by isoprenaline. Prior treatment with LY171883, IBMX, or theophylline did not enhance this action. Isoprenaline reduced histamine‐induced bronchospasm in anaesthetized guinea‐pigs. LY171883, 30 mg kg−1, or IBMX, 1 mg kg−1, did not affect the isoprenaline‐induced decrease in the histamine response. IBMX, 3 mg kg−1, and theophylline, 30 mg kg−1, augmented the isoprenaline‐induced bronchodilation. LTE4‐induced bronchoconstriction was not affected by IBMX or theophylline whereas LY171883 antagonized this response at doses as low as 3 mg kg−1. Therefore, in both in‐vitro and in‐vivo test systems, LY171883 functioned primarily as a leukotriene receptor antagonist with minimal pharmacological activity attributable to its ability to potentiate isoprenaline.