Peter S. Chan

The synthesis of 2,3-dihydro-4(1H)-quinazolinone angiotensin II receptor antagonists

Abstract The synthesis and biological evaluation of a series of 2,3,-dihydro-4-(1H)-quinazolinone angiotensin II receptor antagonists is described.

VPA-985, a nonpeptide orally active and selective vasopressin V2 receptor antagonist.

The introduction of the thiazides as orally-active diuretics about forty years ago (1), and other more effective low-ceiling diuretics thereafter, revolutionized the treatment of edema, ascites, hypertension and related diseases. Later, the addition of potent high-ceiling (loop) and potassium-sparing diuretics provided clinicians with a wide choice of diuretics to eliminate retained sodium and water (2). However, it was soon evident that many patients became refractory to these saluretic agents and some developed hyponatremia (serum sodium < 130 mEq/L) (3, 4, 5). Hyponatremia also occurs in the syndrome of inappropriate antidiuretic hormone secretion (SIADH), in patients with congestive heart failure (CHF), liver cirrhosis with ascites, renal failure, and many other disorders where the plasma vasopressin concentrations are inappropriately high for any given plasma osmolality. Under these conditions, an aquaretic (water diuretic), not a conventional diuretic, would be the drug of choice to promote the excretion of the retained body water and to normalize plasma osmolality and sodium concentration (6, 7, 8). As vasopressin (AVP, antidiuretic hormone (ADH)) acting at V2 receptors in the collecting ducts controls water re-absorption (7, 8), considerable effort has been spent over many years to develop vasopressin Vz receptor antagonists or agents that could inhibit the release of vasopressin from the posterior pituitary (8,9). Many peptide vasopressin analogs have been developed as vasopressin V2 receptor antagonists, and two of them, SK&F 101926 and SK&F 105494, showed excellent V2 antagonistic activity in many animal models, including nonhuman primates. Unfortunately, in humans, both compounds behaved as vasopressin V2 agonists (9). Recently, three nonpeptidic and orally active vasopressin receptor antagonists have been described in the literature. The first two, OPC-31260 (10), and SR 121463A (11), are V2 selective, while the third compound, YM087 (12), is a dual V1a/V2 receptor antagonist.

The synthesis and vasopressin (AVP) antagonist activity of a novel series of N-aroyl-2,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepines.

Synthesis and SAR of N-[4-[(4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-y l)carbonyl]phenyl]benzamides as arginine vasopressin (AVP) receptor antagonists are discussed. Potent orally active AVP receptor antagonists are produced when the benzamide moiety contains a phenyl group at the 2-position. Similar analogues of 4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepine and VPA-985 are reported.

5-fluoro-2-methyl-N-[5-(5H-pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-yl carbonyl)-2-pyridinyl]benzamide (CL-385004) and analogs as orally active arginine vasopressin receptor antagonists.

Synthesis and structure-activity relationships (SAR) of orally active arginine vasopressin (AVP) receptor antagonists are discussed. Potent and orally active AVP receptor antagonists are produced when ring A of VPA-985 (1) is replaced with a 3-pyridinyl unit (2b).

4,10-dihydro-5H-thieno[3,2-c][1]benzazepine derivatives and 9,10-dihydro-4H-thieno[2,3-c][1]benzazepine derivatives as orally active arginine vasopressin receptor antagonists.

Synthesis and structure-activity relationships (SAR) of arginine vasopressin receptor (AVP) antagonists are described. Potent and orally active compounds are prepared when tricyclic 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine moiety in VPA-985 1 is replaced with a compound 7 or 12.

Studies on the Mechanism of the Synergistic Antihypertensive Activity of Captopril and Hydrochlorothiazide Following Acute Administration in Spontaneously Hypertensive Rats

In spontaneously hypertensive rats (SHR), captopril at 30 and hydrochlorothiazide (HCTZ) at 100 mg/kg/day p.o. for 2 days lowered mean arterial blood pressure (MABP) 16 and 10 mm Hg, respectively. Treatment with the combination of captopril plus HCTZ for one day lowered MABP to the same extent as captopril alone, but produced a synergistic 44 mm Hg MABP lowering after the second day combination treatment. Bilateral ureteral ligation did not prevent the synergistic antihypertensive effect demonstrating that removal of electrolytes was not the cause of this effect. Cardiovascular responses to angiotensin-I and -II, norepinephrine or bradykinin did not differ in rats given the combination or captopril alone. After the combination treatment for one day, captopril but not HCTZ alone on the second day lowered MABP in rats to the same degree as in those receiving the combination treatment for 2 days, suggesting that the diuretic action per se is unimportant. Captopril and HCTZ increased plasma renin activity (PRA) but only the combination of captopril and HCTZ produced a greater and longer lasting increase of PRA. It is concluded that the mechanism for the synergism is the renin dependency, created by the combination of HCTZ and captopril, resulting in a greater role of the renin system in blood pressure control and increased responsiveness to angiotensin converting enzyme inhibition by captopril.

2,3,6-Substituted quinazolinones as angiotensin II receptor antagonists

Abstract The synthesis and biological evaluation of a series of 2,3,6-substituted 4(3H)quinazolinones is described. One of these compounds, CL329, 167, was found to be a potent, orally active, competitive angiotensin II receptor antagonist with a long duration of action.

Studies on the Mechanism of the Enhancement of the Antihypertensive Activity of Captopril by A Diuretic in Spontaneously Hypertensive Rats

Captopril (30 mg/kg/day orally for two days) in spontaneously hypertensive rats (SHR) inhibited serum angiotensin converting enzyme (ACE) activity 92.3%; increased plasma renin activity (PRA) 18-fold and reduced mean arterial blood pressure (MABP) 19 mm Hg. Hydrochlorothiazide (HCTZ) (100 mg/kg-day 1; 10 mg/kg-day 2, orally) increased PRA 3-fold but did not affect serum ACE or MABP. HCTZ plus captopril inhibited serum ACE 95.2%; increased PRA 38-fold and reduced MABP 47.5 mm Hg. Captopril or HCTZ plus captopril did not alter the responses of isolated aortic strips to norepinephrine (NE), serotonin, angiotensin II (AII) or isoproterenol. Pressor responses of conscious SHR to AII and NE were unaltered by captopril or HCTZ plus captopril although the bradykinin-induced depressor responses were significantly but equally potentiated. These results suggest that the potentiating effect of HCTZ is due to some mechanism that shifts the animals blood pressure maintenance system to a renin-dependent state and is not due to changes in vascular reactivity.

6-Substituted quinazolinone angiotensin II receptor antagonists

Abstract 4(3H)-quinazolinones with a variety of heterocyclic substituents bound to the 6-position have been synthesized and evaluated as angiotensin II receptor antagonists both in vitro and in vivo. Some of these compounds have been shown to be potent, long-lasting, orally active antihypertensives.

6-isoxazolinyl and isoxazolidinyl substituted quinazolinones as angiotensin II receptor antagonists

Abstract The synthesis and biological evaluation of a series of 4(3H)-quinazolinones substituted at the 6-position with isoxazolines and isoxazolidines is described. Of these, compound 25a was found to be an especially potent, orally active, non-competitive angiotensin II receptor antagonist.