VIEWS & REVIEWS

Companies compete in the development of endothelin receptor antagonists

-Manin Gallagher-

Research chemists from most of the major pharmaceutical companies gathered at the 13th International Symposium on Medicinal Chemistry [Paris, France; September 1994] to compare notes on novel drug design and developmenL Particular interest was shown in the endothelin receptor antagonists, a class of drugs that represents a major avenue of research in the fields of hypertension, stroke, congestive heart failure and acute renal failure.

Endothelial cells playa key role in the dilation of blood vessels in response to acetylcholine. They produce several vasoactive substances, including endothelium-derived relaxing factor (EDRF), which is now assumed to be nitric oxide (NO), and vaso­constrictors such as thromboxane A2 (TXA2) and endothelin-l.

Endothelin-l is a 21-amino acid peptide produced by vascular endothelial cells, and is the most potent vasoconstrictor peptide identified to date. It has a long duration of action that can last up to several hours.

There are now thought to be 3 isopeptides of endo­thelin: endothelin-l, -2 and -3. Only endothelin-l is found in vascular endothelial cells. Endothelin-2 and -3 are found in the brain, kidneys, adrenal glands and intestine.

Endothelin receptors have been divided into 2 groups, endothelinA (ETA) and endothelinB (ET B). ETA receptors interact preferentially with endothelin-l, while ETB has similar affinity for all 3 endothelins. ETA receptors are found on vascular smooth muscle ceHs and may be responsible for vasoconstriction. ET B receptors are found on endothelial cells them­selves, and may be responsible for endothelin-induced production of NO and prostacyclin [see figure 1].

Figure 1: Endothelial receptor Interactions

_____ ET-3

.----_------ ET.1

Endothelial cells

Nitric oxide (EDRF) Prostacyclin

Smooth muscle cells

Relaxation Constriction

Early days yet with Banyu'S receptor IIIl1agon&s Dr Ishikawa from Banyu described the company's

recent work with novel endothelin receptor antag­onists. Banyu began with natural cyclic pentapeptides from which BQ-123 was derived [see figure 2]. N-terminal modification led to BQ-485 and BQ-61O (both ETA-selective) and BQ-788 (ET B-selective). Another compound, BQ-928 is a potent dual antag­onist at ETA and ETB receptors.

In animal studies, BQ-123 appears to have no effect on blood pressure in normotensive rats, but reduces blood pressure in stroke-prone spontaneously

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Figure 2: Compounds derived from 8Q-123

80-123 cyclo( -trp·asp·Pro·val-Leu·)

~

BO-485 N-CO-Leu-trp-trp-OH

"--'

BO·610 C N·CO·Leu·trp(CHO)·trp-OH

BO· 788 C N-co-gamma-MeLeU(C02Me)-nle-oH

hypertensive rats. The development of these compounds is still at the preclinical stage.

Roche enters dinical tl'iUi with Ixlientan At Roche, research began with RO-431736, the

disulfide dimer of the octapeptide endothelin-l, and the weakly active pyrimidine derivative, RO-062687.

A series of more potent compounds eventually led to the development of bosentan [RO-4 70203] [see figure 3]. This sulfonamide compound is orally active (oral bioavailability of 30-80%) and has a lI,'2

of 4-8 hours. Bosentan is currently in phase I trials as a potential treatment for subarachnoid haemorrhage (SAH) and may also be beneficial in the treatment of hypertension .

In preclinical studies, bosentan reversed cerebral vasospasm in a rabbit model of SAH, prevented renal ischaemia in rats and reduced blood pressure in animal models of hypertension, with no effect on heart rate. Bosentan is nonselective for ETA and ETB receptors.

Figure 3: 80sentan

v ~ I ~&...NH # OMe

IB~ ~~O CN~ ~ . . ~ /'-. _OH I 'I' 'N 0-"""

hN

Merck develops nonpeptide rompounds Dr Chakravarty from Merck described the

company's research with a novel series of potent,

INPHARMA- 12 Nov 1l1li4

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4 VIEWS & REVIEWS

Endothelin antagonists- continued

nonpeptide endothelin antagonists with molecular weights in the range 400-500. The most promising candidate, L-747844, has good binding affinity for cloned human ETA (ICso = 48nM) and ET 8 (ICso = 630nM) receptors expressed in Chinese hamster ovarian cells. L-747844, as the bipotassium salt, has good oral bioavailability (26% in the rat) and a half-life of around 2 hours. L-747844 has similar in vivo potency to bosentan and BQ-123.

Dr Walsh, another researcher from Merck, reported on a different series of nonpeptide endothelin antag­onists discovered in a screening programme. The lead compound of this group is L-749329. In vivo, L-749329 blocks the pressor effects of endothelin-I, with a half-life> 2 hours and a duration of action > 6 hours. The oral bioavailability of L-749329 is around 50% in the rat. L-749329 significantly lowers mean arterial pressure in animal models of hyper­tension. Work is currently underway on enantiomers of this compound.

Other agents under development Using a screening strategy, researchers at Parke­

Davis have identified dozens of compounds with potent affinity for endothelin receptors (generally selective for ETA receptors). Of these, PD-155080 and PD-156707 are orally active (oral bioavailability of 50-90%) and have a half-life of 1-5 hours in various animal species.

PD-155080 crosses the blood-brain barrier, blocks endothelin-I-induced vasoconstriction and is effect­ive in the middle cerebral artery occlusion model of stroke. PD-156707 is currently the main development candidate and is undergoing further preclinical evaluation.

Using a rational drug design approach, SmithKline Beecham has developed SB-209670, a potent non­peptide endothelin receptor antagonist (90-fold selectivity for ETA over ET8 receptors). The oral bioavailability of SB-209670 is limited, however, and work is continuing to develop improved compounds. Potential therapeutic indications include hypertension and acute renal failure.

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12 Noy 1994INPHARMAe 0156·270319410963-0004l$01.00° Adl.lnternatlonal Limited 1994. All right. r~