Drug Development Research 4: 179-189 (1984)

Antihypertensive Assessment of Two New Angiotensin-Converting Enzyme Inhibitors: CGS 13945 and CGS 13934 Donald Miller, Barry E. Watkins, Marlene F. Hopkins, Stanley T. Tonnesen, and Donna Van Orsdell

Research Department, Pharmaceuticals Division, CIBA-GEIG Y Corporation, Summit, New Jersey

ABSTRACT

Miller, D., B.E. Watkins, M.F. Hopkins, S.T. Tonnesen, and D. Van Orsdell: Antihy- pertensive assessment of two new angiotensin-converting enzyme (ACE) inhibitors: CGS 13945 and CGS 13934. Drug Dev. Res. 4:179-189, 1984.

CGS 13945 (1 -(4-(ethoxycarbonyl)-2,4-dimethyl-2R,4R-butyryl)-2,3-di hydro-2S-indole-2-car- boxylic acid) and CGS 13934 (its dicarboxylic acid derivative) are nonthiol angiotensin- converting enzyme (ACE) inhibitors which have antihypertensive properties. Acute admin- istration of CGS 13945 lowers systolic pressure in spontaneously hypertensive rats (SHR) and sodium depletion enhances the blood pressure reduction; the acute antihypertensive effects of CGS 13934 are minimal. Acute administration of CGS 13945 or CGS 13934 also elevates plasma renin activity, especially in sodium-depleted SHR. CGS 13945 reduces systolic blood pressure of SHR in a dose-dependent manner following oral administration on each of 4 consecutive days, whereas the antihypertensive effect of CGS 13934 is not apparent until the third day of drug administration. After 3 consecutive daily doses, 30 mg/ kg (PO) of CGS 13945, CGS 13934 or captopril produce equal antihypertensive effects. CGS 13945 also reduces systolic blood pressure of sodium-depleted normotensive rats. Daily oral adminstration of CGS 13945 to either sodium-replete or -deplete perinephritic hypertensive dogs does not appreciably affect mean arterial pressure. Results suggesto that CGS 13945 must be endogenously de-esterified to the free acid form for endowment of optimal biological activity to inhibit the ACE. While the rat is apparently capable of such hydrolysis, the dog’s capacity for endogenous hydrolysis appears to be quite limited.

Key words: CGS 13945, CGS 13934, angiotensin-converting enzyme inhibitor, blood pressure, plasma renin activity, SHR

Received final version September 19, 1983; accepted September 26, 1983.

Address reprint requests to Donald Miller, Research Department, Pharmaceuticals Division, CIBA- GEIGY Corporation, Summit, NJ 07901.

0 1984 Alan R. Liss, Inc.

180 Miller et al.

INTRODUCTION

The renin-angiotensin system constitutes a primary homeostatic mechanism for regula- tion of arterial pressure, electrolyte metabolism, and water balance [Coleman et al., 1975; Davis and Freeman, 1976; Vaughn et al, 1978; Hall et al., 19801. Hypovolemic or vasodepres- sor challenges activate the system, resulting in compensatory adjustments mediated by angi- otensin I1 (AII) which increases total peripheral resistance and promotes salt and water retention.

Pharmacologic inhibition of the renin-angiotensin system has clarified the role of A11 in blood pressure regulation during normal and hypertensive states [Watkins et al., 1976; Bengis et al., 1978; Case et al., 19781. This knowledge has fostered the idea that modulation of the renin-angiotensin system can be an important therapeutic modality for the treatment of hyper- tension [Rubin et al., 1978; Khosla et al., 19791. One susceptible site for intervention by drugs is the angiotensin-converting enzyme (ACE). However, the biological activity profile of such compounds is likely to be rather complex since the ACE has additional actions, including the degradation of kinins [Erdos, 19761 and opiates [Erdos et al., 19781. Captopril, the first orally active ACE inhibitor, lowers arterial pressure effectively in renovascular and essential hyper- tension [Atlas et al., 19791. However, captopril occasionally produces unwanted effects in man which may be related to the presence of a thiol group in its molecule. This has led to the search for nonthiol ACE inhibitors [Gross et al., 1981; Sweet et al., 1981al.

CGS 13945, 1-(4-ethoxycarbonyl-2,4-dimethy1-2R,4R butyryl)-2,3-dihydro-2S-indole- 2-carboxylic acid, and CGS 13934 (its dicarboxylic acid derivative) are nonthiol ACE inhibi- tors. The pharmacological characteristics of the compounds suggest that the esterified com- pound (CGS 13945) may require hydrolysis to generate the biologically active dicarboxylic acid form, CGS 13934 [Chen et al., 19841. There is also evidence that the oral bioavailability of the dicarboxylic acid structure is less than that of the esterified compound. Comparable findings have been reported for a similar nonthiol ACE inhibitor, MK-421 [Sweet et al., 1981al.

This communication describes the effects of CGS 13945 and CGS 13934 on arterial blood pressure in sodium-deplete normotensive rats, sodium-replete or -deplete spontaneously hypertensive rats (SHR), and dogs having chronic perinephritic hypertension.

METHODS Acute Antihypertensive Activity in Sodium-Replete or -Deplete Spontaneously Hypertensive Rats

The acute effects of a single oral dose of CGS 13934, CGS 13945, or captopril on directly measured mean arterial pressure were assessed in SHR fed a normal sodium diet of Wayne Lab-Blox ad libitum, or after active sodium depletion. Sodium depletion was achieved by feeding the rats a sodium-deficient chow (ICN, Cleveland, OH; Hartroft and Eisenstein modification) coupled with administration of hydrochlorothiazide (50 mg/kg, PO) on the first 3 days of dietary sodium restriction.

One day before experimentation, the rats were anesthetized with 0.3 ml of a mixture of ketamine HCI (9 1 mg/ml) and acepromazine maleate (0.9 mg/ml) administered intramuscu- larly. A PE-50 cannula, prefilled with sodium heparin (5,000 units/ml) and sealed at one end, was inserted into the left carotid artery and exteriorized at the nape of the neck. Animals received only tap water (ad libitum) for the next 18 hours. For measurement of arterial pressure, each rat was placed in a Lucite restrainer and its cannula attached to a Could-Statham P23Db pressure transducer connected to a Beckman type R polygraph. Basal mean arterial pressure was measured after the rats had been in restrainers for 1 hour of accommodation. CGS 13934, CGS 13945 or captopril (30 and 100 mg/kg, PO) was administered to separate groups (n = 6) of sodium-replete or -deplete SHR. Similar groups of rats received the

Antihypertensive Assessment of (ACE) Inhibitors 181

cornstarch vehicle. In all groups, mean arterial pressure was monitored continuously for 4 hours after dosing and values were recorded at 30-min intervals. The rats were then sacrificed by decapitation. At this time, 3.0-ml samples of trunk blood were collected in tubes containing 0.025 ml of 10% disodium ethylene-diamine tetraacetic acid (EDTA) for subsequent determi- nation of plasma renin activity (PRA) (Angiotensin I Immutope Kit, E.R. Squibb).

Antihypertensive Activity in Rats Following Repeated Dosing

Male adult SHR (260-430 g; Charles River Breeding Laboratories) were maintained on Wayne Lab-Blox and tap water ad libitum. Blood pressure studies were conducted on conscious SHR in individual Lucite restraint cages. Systolic blood pressure was assessed indirectly from the tail artery using the sphygmometric method of Robson et al. (19781. In separate experi- ments, CGS 13934 (3.0, 10, 30, and 50 mg/kg), CGS 13945 (1.0, 3.0, 10, 30, and 50 mg/kg), or captopril (30 mg/kg) was administered by gavage once daily for 4 consecutive days in an aqueous suspension (1 .O ml/kg) containing 3 % colloidal cornstarch, 5 % PEG-400, and 0.3 % Tween 80. Additional groups of SHR were simultaneously treated with the cornstarch vehicle.

On the first day of the 4-day treatment protocol, blood pressure and heart rate were measured in separate groups of animals (n = 6) prior to drug administration. Each group of rats was then orally dosed with CGS 13934, CGS 13945, captopril, or the cornstarch vehicle, and systolic pressure was measured 2 and 4 hours after dosing. The animals were then returned to their housing until the next morning, when systolic pressure was measured at 24 hours after dosing. The second day’s treatment was then administered and additional measurements made 2, 4, and 24 hours after dosing. This schedule was followed on the third and fourth days of drug administration.

A similar 4-day dosing study was conducted in male adult Wistar rats (300-370 g; Charles River) that had been fed the sodium-deficient rat chow for 35 days prior to the first day of drug treatment. These rats were dosed once daily for 4 consecutive days with furosemide (30 mg/kg, PO) alone or in combination with CGS 13945 (30 mgikg, PO). These drugs were administered orally in an aqueous suspension containing 3 % colloidal cornstarch, 5 % PEG- 400, and 0.3% Tween 80; the volume administered was 1.0 ml/kg. As in the earlier study, systolic pressure was measured prior to initial drug administration, and at 2 and 24 hours after each dosing through 4 days. Five hours after the fourth daily dosing, the rats were sacrificed by decapitation. At this time 3.0-ml samples of trunk blood were collected in tubes containing 0.025 ml of 10% EDTA for subsequent radioimmunological determination of PRA.

Blood Pressure Effects in Sodium-Replete and Sodium-Deplete Perinephritic Hypertensive Dogs Following Repeated Oral Dosing

Blood pressure studies were conducted in conscious chronically hypertensive male mongrel dogs (12-18.5 kg) which were fed a standard chow (Purina Lab Canine Diet 5006). Chronic perinephritic hypertension had been produced by unilateral nephrectomy coupled with wrapping the remaining kidney with cellophane. While the dogs were lying comfortably on a contoured table, arterial pressure was measured by direct percutaneous femoral artery puncture using a 22-gauge needle connected to a Gould-Statham P23Db transducer in series with a Beckrnan polygraph. After collecting initial control data, each group was treated once daily (PO) for 4 consecutive days with gelatin capsules containing 10 mg/kg of CGS 13945 or lactose. For each treatment group, blood pressure measurements were made at 1.5, 3, 6, and 24 hours after each daily dosing. Following a 3-week recovery period, the dogs were identi- cally retested with CGS 13945 in a crossover experimental design after they had undergone active sodium depletion. Sodium depletion was instituted by feeding a sodium-deficient diet (Hill’s “H/D Prescription Diet”) starting 4 days prior to experimentation, coupled with furosemide (20 mg, IM) on the first 2 days of sodium restriction. Throughout this phase of the study the dogs were housed in metabolism cages for measurement of urinary sodium excretion and calculation of the extent of induced sodium depletion.

182 Miller et al.

Test Compounds

CGS 13934 and CGS 13945 were synthesized at CIBA-GEIGY Pharmaceutical Co., Summit, NJ. Captopril used in these studies was either synthesized at CIBA-GEIGY or donated by the Squibb Institute for Medical Research, Princeton, NJ. Furosemide was donated by Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ. Hydrochlorothiazide is a product of CIBA-GEIGY COT.

RESULTS Acute Antihypertensive Activity in Sodium-Replete or Sodium-Deplete SHR

Acute administration of CGS 13934 (30 or 100 mg/kg, PO) did not affect arterial pressure through 4 hours in sodium-replete SHR, and exerted only a slight antihypertensive effect in actively sodium-depleted SHR; results following the 100 mg/kg dose of CGS 13934 are summarized in Figure la. Conversely, a single oral dose of CGS 13945 (30 or 100 mg/kg) significantly lowered arterial pressure of sodium-depleted SHR for at least 2 hours (Fig. lb). In the sodium-depleted state, 30 or 100 mgikg (PO) of CGS 13945 lowered mean arterial pressure by approximately 30 mm Hg and this antihypertensive effect was fully sustained for 4 hours after the 100 mg/kg dose. In both normal and sodium-depleted SHR, the acute blood pressure effects of captopril were similar to those produced by CGS 13945 (Fig. Ic); captopril appeared to be slightly more effective in the sodium-depleted SHR.

In sodium-replete SHR, single administration of captopril or CGS 13934 (100 mg/kg, PO) increased PRA 2- to 3-fold from values obtained in the cornstarch group, but the effect of CGS 13945 was not statistically significant (Table I). Sodium-depleted SHR treated with cornstarch had high PRA levels which were further elevated by 30 mg/kg (PO) of captopril, CGS 13934, or CGS 13945; 100 mg/kg of CGS 13934 or CGS 13945 produced similar PRA elevation (Table I).

Antihypertensive Activity in Rats Following Repeated Dosing

In the SHR, oral administration of 3.0 mg/kg of CGS 13934 did not reduce systolic pressure in SHR throughout the 4-day treatment protocol (Fig. 2a). Higher doses of CGS 13934 (10, 30, or 50 mg/kg/day) were also without appreciable effect on systolic pressure during the first 2 days of treatment; however, systolic pressure was decreased by 35-45 mm Hg when measured at 2 hours after the last two daily dosings. In contrast, the oral doses (1 .O, 3.0, 30, or 50 mg/kg) of CGS 13945 produced prompt dose-related arterial pressure reduc-

TABLE I. Effects of CGS 13934, CGS 13945 or Captopril on Plasma Renin Activity in Sodium-Replete or -Depleted Spontaneously Hypertensive Rats

Plasma renin activity (ng AI/ml/hr) Oral treatment Sodium-replete Sodium-depleted

Vehicle 1.7 f 0.4 5.8 k 0.7 CGS 13934

30 mglkg 2.0 k 0.7 18.9 k 1.6" 100 mg/kg 5.1 k 0.7a 13.6 k 1.1"

CGS 13945 30 rngikg 2.9 f 0.5 13.5 k 2.0"

100 mg/kg 3.1 k 1.1 17.2 k 1.6"

30 mg/kg 1.1 k 0.4 15.8 f 1.9" 100 mg/kg 3.3 k l.oa 13.9 + 1.7"

Captopril

"Different from the corresponding vehicle group (P< 0.05).

Antihypertensive Assessment of (ACE) Inhibitors 183

'O40 - 0 E J=

(a) CGS 13934

0.5 1 2 3 4

(b) CGS 13945

(c) Captopril

I I I I I

0.5 1 2 3 4 Hours After Drug Administration

Fig. 1. Comparison of acute blood pressure effects of CGS 13934, CGS 13945, and captopril in sodium-replete and sodium-depleted SHR. 0, 0 : 30 mg/kg, PO; A, A: 100 mg/kg, PO. Open symbols represent sodium-replete animals; closed symbols represent sodium-depleted animals. Points represent mean values from six animals. *Different from pre-dose value P Q 0.05.

tions. Although the optimum antihypertensive effect (blood pressure reduction of as much as 70 mm Hg) occurred during the last 2 treatment days, a significant fall in arterial pressure also occurred after initial administration of the higher doses of CGS 13945 (Fig. 2b). For compari- son, the optimum antihypertensive potency of CGS 13945 was greater than that of CGS 13934, and CGS 13945 exhibited an earlier onset of action. As shown in Figure 3, the time course of

184 Miller et al.

(a) CGS 13934

10

0

-10

-20 -30

-40

-50 -60

-70

1 '%\ L

3.0 rnglkg M 10 mg/kg 6-d 30 mg/kg o--o 50 mg/kg

-80 1- , I I

1 2 3 4 Day

Responses Measured 2 Hr After Drug Administration

(b) CGS 13945

0 -10 -

-20 -

-30 - *

o*

A* -50 - M 3.0 mg/kg

-60 - p - a 3 0 m g / k g

-70 - -50 mg/kg

-80 1 I 1 1

1 2 3 4

Day Responses Measured 2 Hr After Drug Administration

Fig. 2. Blood pressure effects of 4-day oral dosing with a) CGS 13934, and b) CGS 13945. Systolic blood pressure measured 2 hours after each daily dose. Points represent mean values from six animals. *Different from pre-dose value P < 0.05.

the antihypertensive effect, including magnitude and duration of action, was similar for CGS 13945 and captopril (30 mg/kg/day, PO) but was delayed for CGS 13934.

Oral administration of furosemide for 4 consecutive days did not alter systolic pressure of normotensive rats deprived of dietary sodium. However, rats that received coadministration of furosemide and CGS 13945 (30 mg/kg, PO) did experience arterial pressure reduction of 10-20 mm Hg throughout the 4-day study (Fig. 4). Plasma renin activity averaged 16.6 2.8

Antihypertensive Assessment of (ACE) Inhibitors 185

4 10 -

I

3 10 - CGS 13934

o--Q CGS13945 Captopril

Day 1 Day 3 -60 l / F F / / h

2 24 2 24 2 24 2 24 Hours After Drug Administration

r u

Fig. 3. Comparison of blood pressure effects of CGS 13934, CGS 13945, and captopril in SHR. Each drug was orally administered at 30 mg/kg daily. Systolic blood pressure measured at 2 and 24 hours after each dosing. Points represent mean values from six animals. *Different from pre-dose value P < 0.05.

Day 1 Day 2 Day 3 Day 4 /

Fig. 4. Blood pressure effects of 4-day oral dosing with CGS 13945 (30 mg/kg, PO) in actively sodium- depleted normotensive rats. 0-0, furosemide alone; 0-0, CGS 13945 and furosemide. Points represent mean values from eight animals. *Different from pre-dose values P < 0.05.

186 Miller et al.

nglmllhr in those rats treated for 4 days with furosemide, which was not significantly different from the value of 17.2 -t 3.3 ng/ml/hr in rats that had received coadministration of furosemide with CGS 13945.

Effects of CGS 13945 in Sodium-Replete and Sodium-Deplete Perinephritic Hypertensive Dogs

Repeated oral administration of CGS 13945 (10 mg/kg) for 4 consecutive days did not affect mean arterial pressure in perinephritic hypertensive dogs prior to or following active sodium depletion sufficient to produce a net negative sodium balance of - 110 5 12 mEq (Fig. 5).

DISCUSSION

The SHR is sensitive to the blood pressure lowering effect of ACE inhibition [Antonaccio et al., 1979, 1980; Sweet et al., 1981al. Since CGS 13934 and CGS 13945 are potent inhibitors of the ACE [Chen et al., 19841, they would be expected to demonstrate antihypertensive efficacy in the SHR. Indeed, the acute antihypertensive profile of CGS 13945 was similar to that of captopril in this species. Oral administration of CGS 13945 or captopril promptly lowered arterial pressure in a dose-related manner, although their acute antihypertensive efficacy was somewhat limited. In contrast, oral administration of high doses of CGS 13934, the dicarboxylic acid derivative, had virtually no acute effect on arterial pressure. These findings are consistent with the observation that the capacity of CGS 13934 to inhibit angioten- sin I pressor responsiveness is appreciably diminished after oral administration [Chen et al., 19841. Taken together, these data suggest that the acute oral bioavailability of CGS 13934 is less than that of CGS 13945 in the rat.

Sodium depletion is known to stimulate the renin-angiotensin system and thereby en- hance the blood pressure lowering effectiveness of ACE inhibitors in normotensive and hypertensive states [Watkins et al., 1976; Bengis et al., 1978; Brunner et al., 1980; Sweet et al., 1981a; Lai et al., 19821. Plasma renin activity was high in SHR which had been sodiurn- depleted, and the acute antihypertensive efficacy of CGS 13945 was markedly enhanced in

1 , Day,l, Day 2 Day 3 Day 4

Hours After Drug Administration

3 E

--h-l-T+l 1.5 6 24 1.5 6 24 1.5 6 24 1.5 6 24

Fig. 5. Blood pressure effect of CGS 13945 (10 mg/kg, PO) in sodium-replete and sodium-depleted perinephritic hypertensive dogs. 0-0, sodium-replete; 0-0, sodium-deplete. Points represent mean values from four animals. *Different from pre-dose value P Q 0.05.

Antihypertensive Assessment of (ACE) Inhibitors 187

these animals. Arterial pressure was also decreased following oral administration of CGS 13945 in normotensive rats made sodium-deficient. Acute administration of CGS 13945 elevated PRA, especially in sodium-depleted SHR. This PRA augmentation could be a conse- quence of the reduction of endogenous A11 titers and subsequent interruption of the normal feedback inhibition of A11 on renal renin release; analogous findings have been reported for captopril [Schiffrin et al., 19811.

When administered to SHR for 4 consecutive days, the antihypertensive effects of CGS 13945 were comparable to those produced by equal doses of captopril. Although the higher doses of CGS 13945 or captopril lowered arterial pressure within 2 hours of initial dosing, optimally well-sustained blood pressure reduction was generally achieved after the second day of dosing. In contrast, the highest oral dose of CGS 13934 (50 mg/kg/day) lowered arterial pressure more slowly and less effectively than did CGS 13945. This observation provides further evidence that CGS 13934, despite being intrinsically more potent than CGS 13945 as an ACE inhibitor [Chen et al., 19841, exhibits relatively poor oral bioavailability which compromises its antihypertensive efficacy. The inability of CGS 13945 to lower arterial pressure in either sodium-replete or -deplete perinephritic hypertensive dogs is noteworthy. These data complement similar findings in the dog that CGS 13945 (IV or PO) did not appreciably inhibit angiotensin I (AI) pressor responsiveness while CGS 13934 (IV, but not PO) was an active ACE inhibitor [Chen et al., 19841. Thus, it appears that the dog has only a limited capacity for endogenous hydrolysis of CGS 13945 to the biologically active dicarbox- ylic acid form.

Although the optimum antihypertensive effect of CGS 13934, CGS 13945, and captopril in the SHR did not develop until after 2 days of treatment, the doses used were above those required for rapid (occurring within 30 min) and essentially complete A1 pressor response inhibition in normotensive rats [Chen et al., 19841. Thus, it appears that the entire antihyper- tensive effect of these compounds is not precisely associated with inhibition of plasma ACE. This temporal dissociation between ACE inhibition and optimal blood pressure reduction may relate to the observation that the SHR, though sensitive to the antihypertensive action of ACE inhibitors, nonetheless characteristically exhibits normal or somewhat suppressed PRA [Anton- accio et al., 1979; Sweet et al., 1981al. Because the antihypertensive response and ACE inhibition profile of CGS 13945 are similar to those of captopril in the SHR, it is possible that these two ACE inhibitors may share common mechanisms of action. For instance, the antihy- pertensive action of captopril correlates better with normal arterial wall renin concentration [Assad and Antonaccio, 19821 than with inhibition of A1 pressor responsiveness [Sweet et al., 1981b) or plasma ACE in SHR [Levens et al., 19811. Further, there is evidence that the antihypertensive effect of captopril may result from alteration of relevant kinin, prostaglandin, or opiate mechanisms [Engle et al, 1972; Williams and Hollenberg, 1977; Marks et al., 1980; Moore et al., 1981; Miller et al., 19831, alteration of sympathetic nervous system [Antonaccio and Kerwin, 19811, or renal excretory function [Antonaccio et al., 19791.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the expert technical assistance of Ronald Dotson. We also wish to acknowledge Margaret Glendenning for typing this manuscript and Marjorie Young for preparing the table and figures.

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