Antihypertensive Agents - ACS Publications

3 Antihypertensives Acting by a Peripheral Mechanism

Downloaded by UNIV OF MICHIGAN ANN ARBOR on February 19, 2015 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0027.ch003

JOHN E. FRANCIS Research Department, Pharmaceuticals Division, CIBA-GEIGY Corp., Ardsley, Ν. Y. 10502

The e f f o r t s of m e d i c i n a l researchers i n trying to f i n d antihypertensive agents working by a p e r i p h e r a l mechanism arise from the e x p e c t a t i o n that these agents will e f f e c t good blood pressure c o n t r o l without the c e n t r a l nervous system s i d e e f f e c t s which are observed to some extent w i t h every marketed agent to date which has a strong c e n t r a l component in its mechanism of a c t i o n . Since a n t i h y p e r t e n s i v e therapy, except in emergency treatment, r e q u i r e s drug treatment every day f o r a long p e r i o d of t i m e , perhaps decades, it i s important that the mental and p h y s i c a l c a p a b i l i t i e s of the p a t i e n t be impaired as little as p o s s i b l e . This i s particularly important in those cases where the hypertensive patient feels w e l l despite h i s c o n d i t i o n . P e r i p h e r a l V a s o d i l a t i n g A n t i h y p e r t e n s i v e Agents P e r i p h e r a l l y a c t i n g drugs have not cornered the major share of the a n t i h y p e r t e n s i v e market because of t h e i r own set of serious s i d e e f f e c t s . Agents which act through r e l a x a t i o n of the v a s c u l a t u r e , commonly called p e r i p h e r a l v a s o d i l a t o r s (even though some p e r i p h e r a l v a s o d i l a t o r s do not lower blood p r e s s u r e ) , can cause edema and increased sodium and r e n i n l e v e l s in the blood as w e l l as r e f l e x t a c h y c a r d i a . Edema and elevated sodium l e v e l s can be c o n t r o l l e d by c o - a d m i n i s t r a t i o n of a diuretic. The more recent f i n d i n g that the other two s i d e e f f e c t s can be overcome by β - a d r e n e r g i c b l o c k i n g agents has g r e a t l y increased the market p o t e n t i a l for v a s o d i l a t i n g a n t i h y p e r t e n s i v e s used in combination w i t h diuretics and β-blockers.

Presently on the U.S. market there are three compounds commonly considered as peripheral d i l a t i n g hypotensive agents. These are hydralazine ( I ) , placed on the market i n 1953 by CIBA, diazoxide (II) from Schering i n 1973 and sodium nitroprusside (III) made available by Roche i n 1974.

55

In Antihypertensive Agents; Engelhardt, E.; ACS Symposium Series; American Chemical Society: Washington, DC, 1976.

ANTIHYPERTENSIVE AGENTS

56

Na Fe(CN) NO 2

5

.2H 0 2

NHNH

2


II

III

Diazoxide and sodium nitroprusside, relative newcomers to the market, are indicated only for hypertensive emergencies. This leaves hydralazine as the only drug of this kind available to date on the U.S. market for chronic use. The t o t a l picture of the mechanism of action of hydralazine i s s t i l l not clearly defined but there i s general agreement that direct relaxation of the vasculature leading to reduced peripheral resistance i s the p r i n c i p a l component of i t s mechanism of action. This drug has stood the test of time despite such side effects as headache, tachycardia and a syndrome which resembles acute systemic lupus erythematosus, often called "hydralazine syndrome" (jL). Many attempts have been made to improve hydralazine through structure modification. The early work of the inventor, Jean Druey, at CIBA i n Basle, covered many variations of the structure and the structure-activity relationships established by Druey and his co-workers hold to this day (2, 3). Th most important compounds were those with the phthalazine (IV) and the pyridazine (V) ring systems. e

4

2

5

1 6

IV The following structure-activity relationships were defined: a) For prolonged hypotensive a c t i v i t y , the hydrazino group must be present i n the 1-position of phthalazine or the 3-position of pyridazine. The hydrazino group i s the most important structural feature. b) A c t i v i t y i s retained i n many examples where the other carbon atoms are additionally substituted. c) The benzene ring of phthalazine may be replaced by pyridine.


3.

FRANCIS

Antihypertensives Acting by a Peripheral Mechanism

57


d) Ifydrazones of hydralazine retain a c t i v i t y . Reaction with acids, esters or acid chlorides converts hydralazine to an s-triazolo (3,4-a) phthalazine which i s inactive presumably because the hydrazino group i s tied up i n a stable ring system. An empirical rule defining the minimum requirements for a c t i v i t y i n this type of compound i s i l l u s t r a t e d by structure VI which shows that the -C=N-N«C- moiety must be i n a s i x membered heteroaromatic system with the hydrazino group (or i t s hydrazone) attached to one of the carbons. Ν

Ν

C

C-NHNH,

VI There are some exceptions to the r u l e , namely structures VTI through XI. A l l of these were active i n animal tests but only 1-hydrazinoisoquinoline (VII) showed a c t i v i t y i n man comparable to hydralazine.

X

XI



58


D i h y d r a l a z i n e ( X I I ) , marketed by CIBA. i n Europe, shows l e s s acute t o x i c i t y i n animals than h y d r a l a z i n e (4,5,). Ecarazine ( X I I I ) , sold by Polfa-Pabiance as B i n a z i n , i s a hydrazide of h y d r a l a z i n e , which may i n d i c a t e that other a c y l a t e d d e r i v a t i v e s

NHNH

2

XII

XIII

may be a c t i v e a l s o , provided c y c l i z a t i o n can be avoided. Picod r a l a z i n e (XIV), a c o n s t i t u e n t of V a l l e n e Complex®, i s s o l d by Farmasimes i n Spain and Hydracarbazine (XV), a c o n s t i t u e n t o f Normatensyl®, i s marketed by T h e r a p l i x i n France.

XIV

XV

New compounds continue t o appear i n the l i t e r a t u r e and some are reported to show advantages over h y d r a l a z i n e i n animal s t u d i e s . For example, L-6150 (XVI) i s s a i d t o be l e s s t o x i c a c u t e l y (6). ISF-2123 (XVII) i s more potent i n r a t s and dogs (7). DJ-1461 (XVIII), a hydrazone of h y d r a l a z i n e , i s claimed t o cause c o n s i d e r a b l y l e s s t a c h y c a r d i a (8). To date i t has not been shown that any of these compounds has a s i g n i f i c a n t c l i n i c a l advantage over h y d r a l a z i n e and t h e r e f o r e , over the l a s t twenty-five years, s l i g h t m o d i f i c a t i o n s o f the h y d r a l a z i n e s t r u c t u r e have not produced a b e t t e r drug of t h i s type.


3.


FRANCIS

59

OH C H

N(CH CH OH) 2

2

3\

^CHgCHCEj

2

Ν

Ν

I

I Ν

Ν

NHNH Downloaded by UNIV OF MICHIGAN ANN ARBOR on February 19, 2015 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0027.ch003

2

NHNH

2

XVI

XVIII XVII

Diazoxide (II) has been known since the early I960's (9) and must be considered as a w e l l known lead. I t bears a structural resemblance to the diuretic agent, chlorothiazide (XIX) but, unlike chlorothiazide, i t i s non-diuretic. Analogs have been prepared by scientists at Schering (10) and by a group i n I t a l y (11). The I t a l i a n group reported that compound XX lowers blood pressure and heart rate intravenously i n rats but causes

XIX

XX

XXI atrioventricular block (12). The Schering group has designed pazoxide (XXI), which i s more potent than diazoxide i n the DOCA rat model. I t i s interesting that pazoxide was one of the most potent compounds predicted by a multiple regression analysis of




60

a series of 2H-l,2,4-benzothiadiazine-l,l-dioxides (13). Com parison of "calculated" with observed a c t i v i t i e s i n the DOCA rat lead to the conclusion that maximum a c t i v i t y would be expected for compounds with a) highly l i p o p h i l i c groups at positions 6 and 7, b) a pKa value greater than eight and c) a narrowly defined π factor which i s a measure of the effect of the sub stituent at position 3 and can be calculated from the octanolwater p a r t i t i o n coefficient. Replacement of the -SC^- moiety of the diazoxide ring system by carbonyl leads to an interesting series of compounds, namely the 4-quinazolinones (XXIIa). Extensive synthetic efforts at Pfizer led to the 2-dialkylamino-6,7-dimethoxy-4-quinazolinones which were p a r t i c u l a r l y promising i n dog studies (14). The best of these, compound XXIII, showed good o r a l a c t i v i t y with no influence on heart rate and no sign of tolerance development. Examination of more than f i f t y analogs revealed that the 2-aminoid group might be varied to some extent but the

XXIIa

XXIIb

XXIII

6,7-dimethoxy substitution was essential for high a c t i v i t y . Re placement of the methoxyls with a l k y l , hydrogen, hydroxyl or even 6,7-methylenedioxy diminishes or eliminates a c t i v i t y . Since substitution at the 3-position eliminates a c t i v i t y , this suggests that the 4-hydroxy-quinazoline structure (XXIIb) may be the active species. Structures XXIV and XXV bridge the gap between

the diazoxide series and the 4-hydroxyquinazoline group but none of these compounds showed a c t i v i t y i n the dog at the doses tested (15). Compound XXIII was shown to be active i n man but


3.

FRANCIS


61

was subsequently displaced by compounds i n the 4-aminoquinazoline series which were c l e a r l y more potent i n animal studies (16). The compounds XXVT through XXIX were reported to be more potent than hydralazine i n dogs.


XXVI R= NMe.

XXVII R= -N

/ XXVIII

R= -N

N(CH CH=CH 2

2

/H NCOCH CH[

\

3

2

XXIX R= -N a l l lowered blood pressure and peripheral resistance without tachycardia. The piperazines XXVTII and XXIX were the most potent (20-150 ug/kg o r a l l y ) . Of these four, prazosin (XXIX) has emerged as a potent antihypertensive agent i n c l i n i c a l t r i a l s (17) and has now been marketed i n several countries including the United Kingdom. Trimazosin (XXX), with three methoxyl groups i n the benzene r i n g , has also been shown to be c l i n i c a l l y effective, although i t appears to be less potent than prazosin (18). CHo

0CH

3

Ν

V_y

NCOCHoC—OH

1C H

0

XXX Another potent peripheral vasodilator with hypotensive a c t i v i t y i s minoxidil (U-10,858, XXXI). The drug was developed at the Upjohn Corporation, apparently as a follow-up of a previous c l i n i c a l candidate, diallylmelamine -N-oxide (U-20,388, XXXII). The amine precursor, diallylmelamine (U-7720, XXXIII), i s active i n rats and dogs but not i n man because the active



62

metabolite i s the N-oxide, which does not form i n the human body (19, 20).


2

XXXI

XXXII

XXXIII

C l i n i c a l reports on minoxidil indicate that the drug i s effective, p a r t i c u l a r l y i n cases which are refractory to other drugs (21, 22). I t has the t y p i c a l side-effects of a vasodila tor and co-administrâtion of a diuretic and a β-adrenergic blocker i s recommended i n many of the reported studies (21-28). An unusual and troublesome side-effect, p a r t i c u l a r l y i n women, i s lanugal hair growth (21, 22). An enzyme i n h i b i t o r of microbial o r i g i n with a simple structure, fusaric acid (XXXIV), i s a hypotensive agent. This compound has been tested c l i n i c a l l y as the free acid (29) and as the calcium s a l t (30) and i s o r a l l y effective i n man with a low incidence of side-effects. Dopamine-β-hydroxylase inhibitory action of this compound has been demonstrated i n man (29).

0 XXXIV

XXXV

XXXVI

Introduction of chlorine or bromine into the 3- and/or 4- positions of the side chain yields more potent compounds i n terms of hypotension i n rats and dopamine β- hydroxylase i n h i b i t i o n (31, 32.). The analog YP-279 (XXXV) i s also hypotensive i n rats but i s said not to affect brain norepinephrine bio synthesis unlike fusaric acid or dibromofusaric acid (33-35). Fusaric acid amide (bupicomide, Sch 10595, XXXVI) i s c l i n i c a l l y effective at 300 to 1800 mg per day and i s said to have hemo dynamic effects similar to hydralazine (36, 37). The amide i s


3.

FRANCIS


63


metabolized to the a c i d i n man (38). Turning from p y r i d i n e to d i h y d r o p y r i d i n e , we f i n d another i n t e r e s t i n g s t r u c t u r a l type represented by SKF 24260 (XXXVII). I n dogs, t h i s compound i s a potent, long a c t i n g hypotensive which shows r e f l e x t a c h y c a r d i a but no tolerance p o t e n t i a l (39). I t i s c l o s e l y r e l a t e d to the Bayer compound n i f e d i p i n e c u r r e n t l y under i n v e s t i g a t i o n i n Europe as an a n t i a n g i n a l agent (40). Both drugs are s a i d to lower blood pressure i n man.

An i n v e s t i g a t i o n of more than n i n e t y analogs of XXXVII led to the f o l l o w i n g g e n e r a l i z a t i o n s regarding s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s (41): a) In general, the best compounds have a c y c l i c s u b s t i t u e n t at the 4 - p o s i t i o n , p a r t i c u l a r l y o r t h o - s u b s t i t u t e d a r y l or a heterocycle. b) Methyl groups at p o s i t i o n s 2 and 6 are p r e f e r a b l e to e t h y l or hydrogen. c) Replacement of the e s t e r groups at p o s i t i o n s 3 and 5 by other electron-withdrawing groups lowers a c t i v i t y . d) The e t h y l e s t e r s u s u a l l y have greater o r a l potency than the methyl e s t e r s . e) S u b s t i t u t i o n a t the n i t r o g e n atom lowers a c t i v i t y i n general. Since the p y r i d i n e d e r i v a t i v e s obtained as metabolic products of SKF 24260 are i n a c t i v e (42), the importance of the dihydropyridine s t r u c t u r e i s c l e a r . A mesoionic compound PR-G-138-C1 (XXXIX) from Pharma Research i n Canada i s reported to lower blood pressure i n man a t low doses by a v a s o d i l a t o r type mechanism (43). This s t r u c t u r e i s r e l a t e d to SIN-10 (XL) which was reported e a r l i e r by Japanese s c i e n t i s t s as a c t i v e i n dogs (44). Compounds r e l a t e d to s t r u c t u r e XXXIX were compared i n spontaneous hypertensive r a t s and those w i t h the oxadiazole r i n g hydrogen replaced by c h l o r i n e or bromine were as a c t i v e as the parent compound, although r e placement by methyl caused a l o s s of a c t i v i t y (45).




64

Drugs Affecting Noradrenergic Mechanisms Since the discovery that norepinephrine release at the adrenergic nerve terminal i s the mechanism whereby the human body maintains sympathetic tone, medicinal scientists have searched for agents which reduce sympathetic tone through inter ference with norepinephrine peripherally. Reduction of the effect of norepinephrine should lead to a lowering of blood pressure which might be achieved i n the following ways: a) Adrenergic blockade: Substances which combine with the effector c e l l s and make them unresponsive to norepinephrine cause adrenergic blockade and compounds which appear to i n h i b i t selectively either a- or β-adrenergic receptors can be i d e n t i fied. b) Adrenergic neuronal blockade: In contrast to adrenergic blockers, these agents act within the sympathetic nerves to prevent the release of transmitter amine, thus reducing stimula t i o n at the effector c e l l s without decreasing their responsive ness. c) Inhibition of reuptake and storage: Norepinephrine i s present i n adrenergic nerve terminals i n a bound form i n storage vesicles i n equilibrium with an i n t r a c e l l u l a r pool of the free catechol amine,. Activation of the neuron liberates norepinephrine into the synaptic c l e f t where some of the molecules activate the receptors but most are rapidly drawn back into the nerve terminal as the neuron f i r i n g ceases. An agent may interfere with the reuptake of norepinephrine into the nerve terminal thus prolong ing the time norepinephrine i s present i n the synaptic c l e f t . The catecholamine may then be inactivated through methylation of the meta-hydroxyl group catalyzed by the enzyme catechol-Omethyltransferase. Also, an agent may interfere with reuptake of norepinephrine into storage vesicles which allows the free i n t r a c e l l u l a r pool to be depleted by oxidation catalyzed by monamine oxidase, an enzyme present i n mitochondria within the nerve terminal.



3.

FRANCIS


65

d) Inhibition of biosynthesis: The conversion of tyrosine to norepinephrine v i a dihydroxyphenylalanine (DOPA) and dihydroxyphenethylamine (dopamine) involves three enzymatically controlled steps. Drugs which i n h i b i t these enzymes could be expected to decrease norepinephrine concentration. Since the f i r s t step i s r a t e - l i m i t i n g , tyrosine hydroxylase i n h i b i t i o n should be the most desirable mechanism. e) Norepinephrine release: Agents which release norepinephrine from storage sites may cause a short acting sympathomimetic effect, but the long range effect i s one of depletion i f nor epinephrine i s metabolized rapidly and not replaced by bio synthesis quickly enough. f) Displacement of norepinephrine at storage s i t e s : Some amines related i n structure to norepinephrine may displace molecule for molecule the natural transmitter i n the storage s i t e s . I f these amines are less sympathomimetic they should, when released, produce an attenuated effect on adrenergic receptors, resulting i n lowering of blood pressure. Although β-adrenergic blocking agents have only recently been exploited as potential antihypertensive agents, α-adrenergic blockers have been known since the late 1930's and have received early consideration as hypotensive agents. The drugs phentolamine (XLI), piperoxan (XLII) and phenoxybenzamine (XLIII) are three which were studied c l i n i c a l l y i n depth. These strong α-blocking agents have side effects resulting from the a-blockade,

CH CH C1 XLIII

2

0

z

9

namely increased cardiac rate and force, and postural hypotension, and they are not used alone i n the treatment of hypertension. Phentolamine and phenoxybenzamine are on the U.S. market for use i n the management of pheochromocytoma (46). A successful c l i n i c a l t r i a l of a combination of. phentolamine with the β-adrenergic blocking agent oxprenolol (47), leads to the conclusion that a combination of a - and β-blockers could be a useful method for



66

controlling blood pressure and thus the α-blocking properties of a compound need not be feared. Prazosin (vide supra) has an α-blocking e f f e c t , for example (48). Another compound thought to have a strong α-blocking component as well as a vasodilating effect i s indoramin (XLIV). This indole derivative d i f f e r s from other α-blockers i n that i t depresses cardiac output with the result that, c l i n i c a l l y , tachycardia i s not a serious side effect (49, 50).


0

Indoramin was the product of investigation at Wyeth Labora tories of a number of compounds containing the indolylethylpiperidine group. Structure-activity relationships have been published i n d e t a i l (51-53). The most remarkable findings appear to be that no advantage was gained by extensive modification of the 4-benzamidopiperidine moiety nor by replacement of the indole group by other heterocycles. Replacement of indolylethyl by benzoylpropyl (structure XLV: R=H) produced a compound equipotent i n rats and the p-chloro analog was the most potent α-blocker i n the series. The central nervous system side effects of indoramin may l i m i t i t s u t i l i t y and the close resemblance of XLV to known central nervous system drugs such as haloperidol suggests that this new series w i l l also have central effects. Nonetheless, indoramin appears to be an interesting lead and a focal point of further research. Since ergot alkaloids were the f i r s t adrenergic blocking agents to be discovered, i t i s noteworthy that the ergot deriva tive nicergoline (XLVI) was marketed i n I t a l y by Farmitalia i n 1974, for parenteral treatment of hypertension as w e l l as p e r i pheral and cerebral vasodilatation. I t i s said to have α-blocking (54) and vasodilating properties and i s well tolerated with no undesirable side effects on the heart.



3. FRANCIS


XLVI

67

J H

The A l l e n and Hanburys compound ibidomide (AH 5158, XLVII) i s a combination a- and β-blocker (55, 56), Early c l i n i c a l t r i a l s indicate that i t lowers blood pressure i n man (57) and although the β-blockade i s non-cardioselective, the bronchoconstrictor effects appear to be suppressed by the α-blocking component (58). This p r o f i l e d i f f e r s markedly from that of the

XLVII

XLVIII

close structural analog n y l i d r i n (XLVIII) which i s a β-stimulant possibly effective i n vasospastic disorders (59). The late 1950's and early I960 s saw the emergence of adrenergic neuron blocking agents. Xylocholine (XLIX), struc t u r a l l y similar to the general ganglionic blocking agents, showed some promise as a selective blocker of the peripheral sympathetic system, but since i t showed serious cholinergic side effects i t was undesirable for use i n man (60). 1

XLIX

L



68


Bretylium (L) showed selective adrenergic blocking a c t i v i t y i n animals and man but e r r a t i c absorption and other side effects limited i t s u t i l i t y i n hypertension (61). A significant advance i n this area was the discovery of the CIBA compound SU-4029 (LI).

LI

LII

This amidoxime reduced blood pressure i n renal and neurogenic hypertensive dogs with a slow onset of a c t i v i t y and prolonged action (62). In the c l i n i c , i t was hypotensive i n man but caused elevation of body temperature (63). Extensive structure modifications by Dr. Robert Mull and co-workers at CIBA i n terms of ring size, chain length and end group led to guanethidine (LII) (64). This guanidine had the optimal a c t i v i t y i n the series and i s much superior i n adrenergic neuronal blocking properties to SU 4029. The drug showed a prolonged blood press ure lowering effect i n man, even i n severe cases, with no tachycardia, as expected for such an agent. This was marketed i n 1960 and i s s t i l l the only drug of i t s kind on the U.S. market. Further studies i n animals showed that norepinephrine depletion occurs i n heart but not i n brain and consequently central side effects are minimal. Although there i s no tachy cardia, orthostatic hypotension i s a frequent side effect and diarrhea and i n h i b i t i o n of ejaculation are common reactions. The desirable blood pressure lowering effect coupled with these side effects made attempts to improve on guanethidine worthwhile. There have been many hundreds of publications on guanethidine and a vast number of synthetic variations on the structure. By 1967, five compounds related i n structure to guanethidine had reached the market i n at least one European country (65), namely, guanochlor (Pfizer, L I I I ) , guanacline (Bayer, LIV), guanoxan (Pfizer, LV) bethanidine (Burroughs-Welicorne, LVI) and debrisoquine (Hoffmann-LaRoche, LVII). A l l of these d i f f e r pharmaco l o g i c a l l y from guanethidine to some extent and each i s claimed to show some advantage over guanethidine i n man, such as greater a c t i v i t y i n patients refractory to guanethidine or better control of blood pressure through more frequent dosage.



3. FRANCIS


69

LVII

I n a b i l i t y to gain acceptance on the U.S. market has not d i s couraged a l l efforts i n this f i e l d and three other c l i n i c a l l y effective drugs have been studied extensively, namely guanadrel (Upjohn, LVIII), guanabenz (Wyeth, LIX) and guancydine (Lederle, LX).




70

Guanadrel i s similar to guanethidine but i s believed to cause fewer incidents of diarrhea (66). Guanabenz, a structural hybrid of guanethidine and clonidine, has a p r o f i l e of a c t i v i t y which also appears to be hybrid (67, 68.). I t lowers blood pressure without orthostatic hypotension and diarrhea, but i t causes drowsiness, indicative of a central mode of action (69). At the opposite pole of a c t i v i t y p r o f i l e i s guancydine which appears to have no significant neuronal blocking a c t i v i t y but rather a direct vascular effect (70, 71). Lederle scientists have reported that only the branched chain cyanoguanidines are s i g n i f i c a n t l y active; the guanethidine analog i s inactive (72). The history of the v a r i a t i o n of the guanethidine structure i l l u s t r a t e s that molecular modification can bring about vast changes i n mechanism of action while the desired end result (in this case, hypotension) i s s t i l l achieved. The Rauwolfia alkaloid reserpine, due to i t s strong central component of a c t i v i t y , i s excluded from this review, even though i t has the peripheral effect of releasing norepinephrine from storage sites where i t can be metabolized by monoamine oxidase. This results i n neurotransmitter depletion and i t appears that good blood pressure control would be achieved by a drug which has this peripheral mechanism but lacks the central component. The Mead-Johnson compound MJ-10459-2 (LXI) shows a c t i v i t y i n

. HBr

LXI



3.

FRANCIS


71

several animal models apparently by peripheral norepinephrine depletion with no effect on brain amines. No c l i n i c a l reports have yet appeared but the pharmacological p r o f i l e i n some ways resembles guanethidine and i n others, a "peripherally acting reserpine" (73-76). Inhibition of norepinephrine biosynthesis can be achieved quite well by chronic oral administration of the tyrosine hydro xylase inhibitor α-methyl-p-tyrosine (LXII) but reduction i n blood pressure was not achieved i n patients with essential hypertension (77). Another potent i n h i b i t o r , 3-iodotyrosine (LXIII) was also inactive i n man (78). Apparently, substantial reduction of norepinephrine (50-707 ) i s not enough to achieve the desired effect. When norepinephrine i s substituted i n the storage sites by amines of similar structure which are less agonistic, these agents are called "false transmitters." U n t i l i t s central o

CH-3 l

COOH

LXII

LXIII

mechanism was defined, methyldopa (LXIV) was thought by some to be converted enzymatically to α-methylnorepinephrine (LXV) which was taken up i n peripheral storage sites and subsequently released to cause blood pressure lowering effects (79, 80) by the false transmitter mechanism. Two genuine examples of

OH Cfr

I

LXIV

ι -

LXV



72


peripherally acting false transmitters are metaraminol (LXVI) and p-hydroxynorephedrine (PHN, LXVII), since neither of them penetrate the blood-brain barrier at effective doses, unlike the metaraminol precursor, α-methy1-m-tyrosine (LXVIII) (81, 82). Crout and co-workers observed that metaraminol lowered blood

LXVIII

pressure i n humans at very low doses (83) without central side effects, but since s l i g h t l y higher doses produced strong pressor effects, the drug could not be used safely. PHN, tested by Oates and co-workers (84), has the same type of a c t i v i t y but much weaker potency. This drug also was administered cautiously. To avoid the inherent pressor a c t i v i t y of metaraminol, scientists at Merck, Sharp and Dohme prepared a number of ethers of metaraminol which showed no pressor a c t i v i t y i n animals (85). These ethers were slowly metabolized to metaraminol i n vivo and the false transmitter gradually displaced norepinephrine from peripheral s i t e s , whereupon blood pressure lowering was achieved. Like metaraminol, the ethers did not penetrate the brain appreciably (86). The m-chlorobenzyl ether (LXIX) was the most promising member of the series studied.

LXIX


3.

FRANCIS


73

Substances Interfering with Angiotensin I I The natural blood globulin, angiotensinogen, i s converted by the proteolytic kidney enzyme, renin, to the decapeptide angiotensin I. This substance i s not a pressor agent but i s cleaved by plasma converting enzyme to the powerful vaso constrictor angiotensin I I , an octapeptide.


Angiotensinogen Renin

Angiotensin I Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu [

J

- Converting Enzyme c=-

Angiotensin I I Asp-Arg-Val-Tyr-Ile-His-Pro-Phe Angiotensin I I i s believed to trigger a series of events important i n blood pressure regulation. Inhibition of the effect of this agent, either through competitive i n h i b i t i o n or interference with i t s biosynthesis could reveal the role of this peptide and perhaps lead to a different type of antihypertensive therapy. A rational approach to the target of a competitive i n h i b i t o r would require the synthesis of a number of peptides d i f f e r i n g s l i g h t l y from the angiotensin I I structure followed by b i o l o g i c a l evaluation. When the M e r r i f i e l d method of peptide synthesis was developed (87), this approach became a r e a l i s t i c one. Several groups of investigators have prepared competitive inhibitors which look promising i n v i t r o and i n animal tests (88-96) but the i n h i b i t o r which has attracted the most attention to date i s Sar •'--Ala**-angiotensin I I , (saralasin, LXX) prepared at Norwich Pharmacal Company (97). When administered by i n t r a venous infusion i n patients with high renin hypertension, the synthetic peptide lowered blood pressure e f f e c t i v e l y (98).


74


Saralasin Sar-Arg-Val-Tyr-Ile-His-Pro-Ala


LXX

From an e n t i r e l y d i f f e r e n t source, namely, the venom of the snake Bothrops j a r a r a c a , s c i e n t i s t s a t Squibb i s o l a t e d a nonapeptide (SQ 20,881, LXXI) which i s a potent i n h i b i t o r of the converting enzyme (99).

f SQ 20,881 p-Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro

LXXI

Comparison of SQ 20,881 with f i f t y - s e v e n r e l a t e d s y n t h e t i c peptides i n d i c a t e d that the l a s t f i v e amino a c i d s of the sequence are required f o r s i g n i f i c a n t enzyme i n h i b i t i n g a c t i v i t y (100). This nonapeptide, i n t r a v e n o u s l y , lowered blood pressure even i n p a t i e n t s with normal r e n i n l e v e l s (101, 102). This e f f e c t i s s t r o n g l y augmented by sodium d e p l e t i o n . The i n t e r e s t i n these peptides and others whose mechanisms of a c t i o n are not yet so c l e a r l y d e f i n e d i s evident from the many recent p u b l i c a t i o n s . Since the peptides are not o r a l l y a c t i v e , t h e i r r o l e i n the treatment of hypertension i s u n c e r t a i n at t h i s p o i n t . T h e i r value as d i a g n o s t i c t o o l s has been e s t a b l i s h e d . For example, the use of s a r a l a s i n i n the r e c o g n i t i o n of angiotensinogenic hypertension i n man has been demonstrated (103). Perhaps of g r e a t e r value w i l l be the r o l e of these compounds and peptides s t i l l to come i n d e f i n i n g the importance of the r e n i n - a n g i o t e n s i n system i n the e t i o l o g y of hypertension and the c o n t r o l of blood pressure.


3.

FRANCIS


75

References C i t e d 1. " P h y s i c i a n s Desk Reference", 29th Ed., p. 687, M e d i c a l Economics Co., O r a d e l l , N.J. (1975) 2. Druey, J . and Marxer, A., J . Med. Pharm. Chem. (1959)


1, 1. 3. Druey, J . and T r i p o d , J . , "Antihypertensive Agents", pp. 223262, ed. E. Schlittler, Academic Press, New York (1967). 4. Gross, F., Druey, J . and Meier, R., E x p e r i e n t i a (1950) 6, 19. 5. Walker, Η., Wilson, S., A t k i n s , Ε., G a r r e t t , H. and Richardson, Α., J . Pharmacol. E x p t l . Therap., (1951) 101, 368. 6. B a l d o l i , Ε., S a r d i , Α., Dezulian, V., C a p e l l i n i , M. and B i a n c h i , G., Arzneim.-forsch.(1973) 23, 1591. 7. C a r p i , C. and D o r i g o t t i , L., B r i t . J . Pharmacol. (1974) 52, 459P. 8. A k a s h i , Α., Chiba, T. and Kasahara, Α., Europ. J. Pharmacol. (1974) 29, 161. 9. Rubin, Α., Roth, F., Winburg, Μ., T o p l i s s , J . , Sherlock, Μ., Sperber, N. and Black, J., Science (1961) 133, 2067. 10. T o p l i s s , J . , Sherlock, Μ., Reimann, H., Konzelman, L., Shapiro, Ε., P e t t e r s e n , Β., Schneider, H. and Sperber, Ν., J . Med. Chem. (1963) 6, 122. 11. R a f f a , L., Lilla, L. and Grana, Ε., Farmaco, Ed. S c i . (1965) 20, 647. 12. R a f f a , L., D i B e l l a , Μ., F e r r a r i , P., R i n a l d i , M. and F e r r a r i , W., Farmaco, Ed. Sci. (1974) 29, 411. 13. T o p l i s s , J . and Yudis, M., J . Med. Chem. (1972) 15, 394. 14. Hess, H.-J., Cronin, T. and S c r i a b i n e , Α., J . Med. Chem. (1968) 11, 130. 15. Cronin, T. and Hess, H.-J., J . Med. Chem. (1968) 11, 136. 16. S c r i a b i n e , Α., Constantine, J . , Hess, H.-J. and McShane, W., E x p e r i e n t i a (1968) 24, 1150. 17. For a recent survey, see " P r a z o s i n - E v a l u a t i o n of a new antihypertensive agent." Proc. of a Symposium held a t the Centre I n t e r p r o f . Geneva (8.3.74) - Amsterdam. Exerpta Med./New York, E l s e l v i e r (1974). 18. DeGuia, D., Mendlowitz, Μ., Russo, C., V l a c h a k i s , N. and Antram, S., Curr. Ther. Res. (1973) 15, 339. 19. Z i n s , G., J . Pharmacol. E x p t l . Therap. (1965) 150, 109. 20. Z i n s , G., Emmert, D. and Walk, R., J . Pharmacol. E x p t l . Therap. (1968) 159, 194. 21. P e t t i n g e r , W. and Mitchell, Η., New Eng. J . Med. (1973) 289 167; C l i n . Pharmacol. Therap. (1973) 14, 143. 22. Bennett, C. and Wilburn, R., C l i n . Res. (1974) 22, 262A. 23. Kincaid-Smith, P., Amer. J . C a r d i o l . (1973) 32, 575. 24. Chidsey, C., C l i n . S c i . Molec. Med. (1973) 45 (Suppl. I ) 171s. 25. P e t t i n g e r , W., Campbell, W. and Keeton, Κ., C i r c u l a t i o n Res. (1973) 33, 82.



76


26. O'Malley, Κ., Velasco, M. and McNay, J . , C l i n . Res. (1973) 21, 953. 27. Pettinger, W. and Keeton, Κ., C l i n . Res. (1973) 21, 472. 28. Ryan, J. Jain, A. and McMahon, F., Curr. Therap. Res. (1975) 17, 55. 29. Matta, R. and Wooten, G., C l i n . Pharmacol. Ther. (1973) 14, (4-I) 54. 30. Hidaka, Η., Nagasaka, A. and Takeda, Α., J . C l i n . Endocrinol. and Metabolism (1973) 37, 145. 31. Hidaka, Η., Asano, T. and Takemoto, N., Mol. Pharmacol. (1973) 9, 172. 32. Ishii, Y., Fujii, Y. and Umezawa, H., Jap. J. Pharmacol. (1973) 23, Suppl., 53 (Abstr. 76). 33. Hidaka, H., Hara, F., Harada, N., Hashizume, Y. and Yano, Μ., J. Pharmacol. Exptl. Therap. (1974) 191, 384 34. Hidaka, Η., Hara, F., Harada, N. and Asano, M., Jap. J . Pharmacol. (1974) 24, (Suppl.) 25 (Abstr. 5). 35. Harada, N. Hashizume, Y. and Hidaka, H., Jap. J . Pharmacol. (1974) 24 (Suppl.) 77 (Abstr. 110). 36. Velasco, Μ., Gilbert, C., Rutledge, C. and McNay, J . , Circulation (1974) 50 (III) 105, abstr. 412. 37. Velasco, M. and McNay, J . , C l i n . Pharmacol. Ther. (1974) 15, 222. 38. Symchowicz., S. and Staub, M., J . Pharmacol. Exptl. Therap. (1974) 191, 324. 39. Loev, B., Ehrreich, S. and Tedeschi, R., J . Pharm. Pharmac o l . (1972) 24, 917. 40. Vater, W., Kroneberg, G., Hoffmeister, F., K a l l e r , Η., Meng, Κ., Oberdorf, Α., Puls, W., Schlossmann, K. and Stoepel, Κ., Arzneim.-forsch. (1972) 22, 1 and succeeding articles. 41. Loev, Β., Goodman, Μ., Snader, Κ., Tedeschi, R. and Macko, E., J. Med. Chem. (1974) 17, 956. 42. Petta, J . and McLean, R., quoted in Walkenstein, S., Intoccia, Α., Flanagan, T., Hwang, Β., Flint, D., Weinstock, J . , Villani, Α., Blackburn, D. and Green, Η., J. Pharm. Sci. (1973) 62, 580. 43. Ryan, J . , Blumenthal, H. and McMahon, F., C l i n . Pharm. Ther. (1975) 17, 243. 44. Takenaka, F., Takeya, Ν., Ishihara, T., Inoue, S., Tsutsumi, E., Nakamura, R., Mitsufiyi, Y. and Sumie, M., Jap. J . Pharmacol. (1970) 20, 253. 45. Goetz, M., Grozinger, K. and Oliver, J . , J. Med. Chem. (1973) 16, 671. 46. "Physicians Desk Reference," 29th. Ed., pp. 708, 1380, Medical Economics Co., Oradell, N. J . (1975). 47. Majid, P., Meevan, M., Benaim, M., Sherma, B. and Taylor, S., B r i t . Heart. J. (1974) 36, 588.



3.

FRANCIS


77

48. Constantine, J., McShane, W., Scriabine, A. and Hess, H.-J., "Hypertension: Mechanisms and Management." Section VI, "Recent Advances in Drug Therapy," p. 429, 26th Hahnemann Symposium, Ed. Onesti, G., Kim, K. and Moyer, J . , Grune and Stratton, New York (1973). 49. Lewis, P., George, C. and Dollery C., Europ. J. C l i n . Pharmacol. (1973) 6, 211. 50. White, C., Royds, R. and Turner, P., Postgrad. Med. J . (1974) 50, 729. 51. Archibald, J . , Alps, B., Cavalla, J . and Jackson, J . , J . Med. Chem. (1971) 14, 1054. 52. Archibald, J . and Benke, G., J . Med. Chem. (1974) 17, 736. 53. Archibald, J . , Fairbrother, P. and Jackson, J . , J. Med. Chem. (1974) 17, 739. 54. Dorigotti, L. and Glasser, Α., Pharmacol. Res. Commun., (1972) 4, 151. 55. Farmer, J . , Kennedy, I . , Levy, G. and Marshall, R., Brit. J. Pharmacol. (1972) 45, 660. 56. C o l l i e r , J . , Dawnay, N., Nachev, C. and Robinson, Β., B r i t . J. Pharmacol. (1972) 44, 286. 57. Richards, D., Woodings, Ε., Stephens, M. and Maconochie, J . , B r i t . J. C l i n . Pharmacol. (1974) 1, 505. 58. Skinner, C., Gaddie, J . and Palmer, Κ., Br. Med. J . (1975) 2, (5962) 59. 59. "Physicians Desk Reference," 29th Ed., p. 1489, Medical Economics Co., Oradell, N.J. (1975). 60. Exley, Κ., Brit. J. Pharmacol. (1957) 12, 297. 61. Boura, Α., Green, Α., McCoubrey, Α., Lawrence, D., Moulton, R. and Rosenheim, J . , Lancet (1959)II,17. 62. Maxwell, R., Ross, S. and Plummer, Α., J . Pharmacol. Exptl. Therap. (1958) 123, 128. 63. Page, I. and Dustan, Η., J.A.M.A. (1959) 170, 1265. 64. M u l l , R. and Maxwell, R., "Antihypertensive Agents," pp. 115-149, ed. E. Schlittler, Academic Press, New York, (1967). 65. deHaen, P., C l i n . Pharmacol. Ther. (1974) 16, (3-I), 413. 66. Hansson, L., Pascual, A. and J u l i u s , S., Clin. Pharmacol. Therap. (1973) 14, 204. 67. Bolme, P., Corrodi, H. and Fuxe, Κ., Acta, Pharmacol. Toxicol. (1972) 31, (Suppl. I) 65. 68. S a i n i , R., Caputi, A. and Marmo, Ε., Farmaco, Ed. Prat. (1973) 28, 359. 69. McMahon, F. G., Cole, P., Boyles, P. and Vanov, S., Curr. Ther. Res. (1974) 16, 389. 70. Sternberg, J . , Sannerstedt, R. and Werkő, L., Europ. J . Clin. Pharmacol. (1971) 3, 63. 71. Ellenbogen, L., Chan, P. and Cummings, J . , Arch. Int. Pharmacodyn. (1974) 207, 170. 72. Gadekar, S., N i b i , S. and Cohen, E., J . Med. Chem. 11, 811 (1968).



78


73. M a t i e r , W., Owens, D., Comer, W., Deitchmann, D., Ferguson, H., Seidehamel, R. and Young, J . , J . Med. Chem. (1973) 16, 901. 74. Perhach, J . , Gomoll, Α., Ferguson, H. and McKinney, G., Fed. Proc. (1974) 33, 485, Abstr. 1551. 75. Deitchmann, D. and Gomoll, Α., Fed. Proc. (1974) 33, 485 Abstr. 1552. 76. Deitchmann, D., Gomoll, Α., Snyder, R., and Preston, J., Arch. I n t . Pharmacodyn. (1974) 210, 268. 77. Engelman, K., Horwitz, D., Jequier, E. and Sjoerdsma, Α., J . C l i n . Invest. (1968) 47, 577. 78. Engelman, K. and Sjoerdsma, A., C i r c u l a t i o n Res. (1966) 18/19, Suppl. I , 104. 79. Day, M. and Rand, M., J . Pharm. Pharmacol. (1963) 15, 221. 80. Day, M. and Rand, Μ., Brit. J . Pharmacol. (1964) 22, 72. 81. Horwitz, D. and Sjoerdsma, Α., Life Sci. (1964) 3, 41. 82. Holtmeier, Η., vonKlein-Wisenberg, A. and Marongiu, F., Deutsche Med. Wochen. (1966) 91, 198. 83. Crout, J . , Johnston, R., Webb, W. and Shore, P., C l i n . Res. (1965) 13, 204. 84. Rangno, R., Kaufman, J . , Cavanaugh, J . , I s l a n d , D., Watson, J . and Oates, J., J . Clin. Invest. (1973) 52, 952. 85. S a a r i , W., Raab, Α., Staas, W., Torchiana, Μ., P o r t e r , C. and Stone, C., J . Med. Chem. (1970) 13, 1057. 86. Torchiana, Μ., P o r t e r , C., Stone, C., Watson, L., S c r i a b i n e , A. and Hanson, Η., Biochem. Pharmacol. (1971) 20, 1537. 87. Merrifield, R., J . Am. Chem. Soc. (1963) 85, 2149. 88. Bumpus, F., Sen, S., Smeby, R., Sweet, C., F e r r a r i o , C. and Khosla, Μ., C i r c u l a t i o n Res. (1973) 32/33 (Suppl.I) I-150. 89. Khosla, Μ., H a l l , Μ., Smeby, R. and Bumpus, F., J . Med. Chem. (1974) 17, 431. 90. Park, W., Choi, C., Rioux, F. and R e g o l i , D., Can. J . Biochem. (1974) 52, 113. 91. Paiva, T., G o i s s i s , G., J u l i a n o , L., Miyamoto, M. and Paiva, Α., J . Med. Chem. (1974) 17, 238. 92. Jorgensen, E., K i r a l y - O l a h , I . , Lee, T. and Windridge, G., J . Med. Chem. (1974) 17, 323. 93. Khosla, Μ., H a l l , Μ., Smeby, R. and Bumpus, F., J . Med. Chem. (1974) 17, 1156. 94. Sen, S., Smeby, R. and Bumpus, F., Proc. Soc. Exp. Biol. Med. (1974) 147, 847. 95. Pena, C., Stewart, J . and Goodfriend, T., Life S c i . (1974) 14, 1331. 96. Wissmann, Η., Schoelkens, Β., Lindner, E. and Geiger, R., Hoppe-Seylers Z. P h y s i o l . Chem. (1974) 355, 1083. 97. P a l s , D., Masucci, F., Denning, G., Sipos, F. and F e s s l e r , D., C i r c u l a t i o n Res. (1971) 29, 673.



3.

FRANCIS


79

98. Brunner, Η., Gavras, H., Laragh, J . and Keenan, R., Lancet (1973) II, 1045. 99. O n d e t t i , Μ., W i l l i a m s , N., Sabo, E., Pluscec, J . , Weaver, E. and Kocy, O., Biochemistry (1971) 10, 4033. 100. Cushman, D., Pluscec, J . , W i l l i a m s , Ν., Weaver, Ε., Sabo, Ε., Kocy, O., Cheung, H. and O n d e t t i , Μ., E x p e r i e n t i a (1973) 29, 1032. 101. Black, W., Shenouda, Α., Johnson, J . , Share, L., Shade, R., Friedman, Β., A c c h i a r d o , S., Vukovich, R., Hatch, F. and Muirhead, Ε., Clin. Res. (1974) 22, 263A. 102. Gavras, Η., Brunner, Η., Laragh, J . , Sealey, J . , Gavras, I . and Vukovich, R., New E n g l . J . Med. (1974) 291, 817. 103. Anderson, G., F r e i b e r g , J . , Dalakos, T. and Streeten, D., Clin. Res. (1974) 22, 257A.


Antihypertensive Agents - ACS Publications

Recommend Documents