Antihypertensive activities

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

P-Adrenoceptor Blockers. There is no satisfactory mechanism to explain the antihypertensive activity of P-adrenoceptor blockers (see Table 1) in humans particularly after chronic treatment (228,231—233). Reductions in heart rate correlate well with decreases in blood pressure and this may be an important mechanism. Other proposed mechanisms include reduction in PRA, reduction in cardiac output, and a central action. However, pindolol produces an antihypertensive effect without lowering PRA. In long-term treatment, the cardiac output is restored despite the decrease in arterial blood pressure and total peripheral resistance. Atenolol (Table 1), which does not penetrate into the brain is an efficacious antihypertensive agent. In short-term treatment, the blood flow to most organs (except the brain) is reduced and the total peripheral resistance may increase. 

The antihypertensive activity of 8-aryl-6,9n-dimethyl-2,3,4,8,9,9n-hexahy-dropyrido[2,l-Z)][l,3]oxazine-7,9-dicarboxylates 79 was evaluated in conscious spontaneously hypertensive rats. They resulted in potent and long-lasting antihypertensive action (97MI14). 

The guanidine function, when attached to an appropriate lipophilic function, often yields compounds that exhibit antihypertensive activity by means of their peripheral sympathetic blocking effects. Attachment of an aromatic ring via a phenolic ether seems to fulfill these structural requirements. Alkylation of 2,6-dichlorophenol with bromochloroethane leads to the intermediate, 58. Alkylation of hydrazine with that halide gives 59. Reaction of the hydrazine with S-methylthiourea affords the guanidine, guanoclor (60). ... 

The benzazepines are not as important pharmacologically as their more famous relatives the benzodiazepines. However, 3-aryl-2-(piperazin-l-yl)-5//-l-benzazepines, e.g. 14, and 17/-3-benzazepin-2-amines 15 possess neuroleptic activity,60 and antihypertensive activity,45 61 respectively. 

A series of corresponding ergoline and ergolene derivatives was synthesized. The ergotamine derivative showed an interesting antihypertensive activity. Unfortunately, the substance has very poor solubility and stability and therefore the further pharmacological evaluation was stopped (ref. 25). 

Casein-derived phosphorylated peptides are believed to enhance the bioavailability of calcium from milk and dairy products (Pihlanto and Korhonen, 2003), and a phosphopeptide derived from (3-casein has been shown to increase iron bioavailability (Bouhallab et ah, 2002 Peres, 1999). Other casein-derived peptides have been found to contain antihypertensive activity in rats (Leclerc et ah, 2002 Miguel et ah, 2009). A number of casein fragments demonstrate antibacterial activity (Kilara and Panyam, 2003). 

The renaissance of the Biginelli MCR can be attributed to the obtained pyrimidine derivatives, which show remarkable pharmacological activity. A broad range of effects, including antiviral, antitumor, antibacterial, anti-inflammatory as well as antihypertensive activities has been ascribed to these partly reduced pyrimidine derivatives [96], such as 9-117 and 9-118 (antihypertensive agents) [97] and 9-119 (ala-adrenoceptor-selective antagonist) [98] (Scheme 9.24). Recently, the scope of this pharmacophore has been further increased by the identification of the 4-(3-hydroxyphenyl)-pyrimidin-2-thione derivative 9-120 known as monastrol [98], a novel cell-permeable lead molecule for the development of new anticancer drugs. Monastrol appears specifically to affect cell division (mitosis) by a new mechanism,... 

Mesoionic oxatriazolium-5-amenates 83 exhibit the whole range of biological properties typical of NO-releasing compounds that stimulate soluble guanylate cyclase namely antihypertensive activity in animals following the relaxation of the vascular... 

The medicinal chemist expects to find that a review written specifically for him will he mainly concerned with a discussion of structure/activity relationships. In the case of the antihypertensive activity of the (3-blockers such a discussion is not possible since no direct comparative activity data is available either from the laboratory or the clinic (the few comparative clinical studies are in no way definitive - see later). It is however possible to approach the problem somewhat indirectly and consider the influence of chemical structure on those pharma -cological properties which appear most relevant to the specific clinical effect. I propose therefore to -... 

There appears to be no relationship between the antihypertensive activity of the 3-blocking agents and the other three laboratory pharmacological parameters. 

Figure 27. Comparison of the relationship between antihypertensive and sympathomimetic activity and sedation and inhibition of gastric secretion of clonidine and two derivatives (St 600 and St 608). The antihypertensive activity was tested in genetic hypertensive rats. The sympathomimetic activity was measured as blood pressure increase in spinal rats. The sleep effect in chicks was tested according to the method in Reference 50, and the gastric secretion in rats was measured according to the method in Reference 57.

Pildralazine (65), when administered i.v. or orally, displays a high antihypertensive activity in conscious hypertensive animals (rats, dogs). The hypotensive effect, caused by oral doses of 0.1 mg/kg to 1 mg/kg, has been reported to last more than 24 h. The therapeutic index (LD50/ED25 rats oral administration) has been found to be 70-times higher than that of hydralazine due to both higher potency and reduced toxicity [197]. It has been concluded that (65), like hydralazine, acts on peripheral smooth muscle on specific receptors which are physiologically affected by ATP released from... 

There are numerous patents claiming 3-hydrazinopyridazine derivatives with amino-substituted alkoxy side-chains at C-6 as ff-blocking vasodilating agents [188,286-293]. Other 3-hydrazinopyridazine-derived antihypertensive agents are covered by patents [294-301], or described in the literature [302 306]. It should be noted that with structurally very simple hydrazino-pyridazines like 6-hydrazino-3-pyridazinecarboxamide (hydracarbazine, 2105 TH CAS 3164-47-9), antihypertensive activity has been observed. 

In Spain, various 6-phenyl-5-aminomethyl-3-hydrazinopyridazines have been prepared and investigated [307]. The antihypertensive activity of compounds of type (75) has been found to exceed the activity of hydralazine. Similar activity has been observed with compound (76) [308]. The activity of the 4-piperazinopyridazine derivative (77) was found to equal that of hydralazine [309]. Also replacement of the phenylpiperazinomethyl substituent in compound (75) by a morpholinomethyl group was found to afford antihypertensive agents [310]. 

In addition to the hydrazinopyridazine derivatives discussed above, a wide variety of pyridazinones and 4,5-dihydropyridazinones exhibit interesting antihypertensive activity. Some selected examples of such compounds claimed in patents are given in formulae (78) [18-20,51,111,116,129,311-335], (79) [169,336], (80) [169,337], (81) [338-341], (82) [52-56,59,60, 127,342-357], (83) [358-362], and (84) [363-365], For many of these compounds also cardiotonic and/or antithrombotic activity has been claimed (compare Part 1 of this review [1]). 

The association of peak antihypertensive activity with the eight-membered ring of guanethidine rather than other ring sizes has been discussed previously... 

R Adrenergic neurone blocking activity Antihypertensive activity... 

The antihypertensive activity of the seven-membered analogue of guanethidine in which a benzene ring is fused in the 4,5-position was reported in the review by... 

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