Synthesis and biological activity of spirocyclic benzopyran imidazolone potassium channel openers.

A series of novel spirocyclic benzopyran imidazolones were synthesized as rigid analogues of cromakalim. These compounds cause a dose-dependent membrane hyperpolarization of A10 rat aorta cells. This hyperpolarization was blocked by pretreatment with glyburide, indicating that the spirocyclic benzopyran imidazolones were acting by increasing the open probability of ATP-sensitive potassium channels in A10 cells. Representative compounds also showed potent in vivo activity as hypotensive agents in normotensive rats. Many of the compounds described are much more potent than cromakalim both in vitro and in vivo, with one of the most potent compounds being 2,3-dihydro-2,2-dimethyl-6-nitro-2'-(propylamino)spiro[4H-1-benzopyran- 4,4'-[4H]imidazol]-5'(1'H)-one (5r). It is concluded that the N1' nitrogen of the imidazolone is an effective substitute for the carbonyl oxygen of cromakalim. The rigid spirocyclic ring fusion holds this nitrogen in an optimum orientation relative to the benzopyran ring.

Synthesis and renin inhibitory activity of angiotensinogen analogues having dehydrostatine, Leu psi [CH2S]Val, or Leu psi [CH2SO]Val at the P1-P1' cleavage site.

The synthesis and in vitro renin inhibitory potencies of angiotensinogen (ANG) analogues having amide (CONH) bond replacements at P1-P1', the Leu-Val cleavage site, corresponding to Leu psi[CH2SO]Val, and the trans olefinic analogue of statine (Sta), 4(S)-amino-6-methyl-2(E)-heptenoic acid (dehydrostatine, Dhs), are reported. These are compared to P1-P1' Leu psi[CH2NH]Val-, Sta-, or Phe-Phe-substituted analogues of the same template. The Dhs pseudodipeptide was found to be an adequate mimic of a trans CONH bond and gave a peptide, H-Pro-His-Pro-Phe-His-Dhs-Ile-His-D-Lys-OH, approximately equal in potency to a Phe-Phe-containing inhibitor, but 200-fold less potent than its Sta-substituted congener. That the enhanced potency of the Sta-containing peptide most likely depends on hydrogen bonding as well as tetrahedral geometry is indicated by the 50-100-fold lower potency of the tetrahedral Leu psi[CH2S]Val and Leu psi[CH2SO]Val analogues as compared to the Leu psi[CH2NH]Val-containing congener.

7-(Trifluoromethyl)-4-aminoquinoline hypotensives: novel peripheral sympatholytics.

A family of 7-(trifluoromethyl)-4-aminoquinolines that are hypotensive agents and that act by a novel sympatholytic mechanism is described. Structure-activity relationships in this series have been elucidated. Some of the more potent hypotensives were evaluated for safety in the mouse. A candidate, 1-[(4-fluorophenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4- quinolinyl]amino]benzoyl]piperazine hydrochloride (losulazine hydrochloride) has been selected for clinical development. Losulazine hydrochloride is a hypotensive agent in the rat, cat, and dog. At acute effective hypotensive doses, it does not block the response of the sympathetic nervous system to stimuli. Both animal pharmacology and clinical experience suggest that losulazine hydrochloride may be free of the clinically limiting side effects that often plague compounds that decrease blood pressure by interfering with autonomic neurogenic function.

1-(alkylamino)isochromans: hypotensives with peripheral and central activities.

A series of 1-[1-(3,4-dimethoxy-1H-2-benzopyran-1-yl)alkyl]-4-arylpiperazines that shows hypotensive activity in the conscious rat has been investigated. Structure-activity relationships are described. A typical example that was investigated in greater detail is 1-[2-(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-(4-fluorophenyl)piperazine. This compound decreases sympathetic nerve activity recorded from the external carotid and splanchnic nerves of baroreceptor-denervated cats and, therefore, has a central component to its mechanism of action. It also blocks pressor effects of norepinephrine and phenylephrine and is thus an alpha-adrenergic antagonist. Binding data characterize this as alpha 1-adrenergic receptor blockade.

Pharmacology of some metabolites of triazolam, alprazolam, and diazepam prepared by a simple, one-step oxidation of benzodiazepines.

A simple, one-step chemical oxidation of triazolam (7) to its 4-hydroxy analogue, 7a, has been developed and applied to other triazolo- and imidazobenzodiazepines. The reaction may be used to convert diazepam to temazepam. 4-Hydroxytriazolo[4,3-a][1,4]benzodiazepines have low central nervous system sedative and anticonvulsant activity in sharp contrast to metabolites of diazepam which remain active. While 10, an alpha-hydroxy metabolite of triazolam, retains much of the activity of 7, 10a, and alpha,4-dihydroxy metabolite of triazolam, is 250 times less potent than 7 on the nicotine-antagonism assay and over 300 times less potent on the traction assay.

Conformationally defined adrenergic agents I: potentiation of levarterenol in rat vas deferens by endo- and exo- 2- aminobenzobicyclo[2.2.2]octenes, conformationally defined analogs of amphetamine.

Four conformationally defined analogs of amphetamine were synthesized and studied for their ability to potentiate the action of levarterenol on the isolated vas deferens from reserpine-treated rats. The compunds also were studied for indirect adrenergic agonist activity in the same test system. A definite stereochemical correlation was demonstrated in each case, the exo-isomers being considerably more active than their endo-counterparts both in potentiation and in indirect activity. The more active isomers of each pair correspond to an anti-periplanar conformation of amphetamine. The compounds are probably acting by inhibition of the neuronal amine uptake mechanism, since none of the compounds was a direct-acting agonist itself. These results are discussed in relationship to other previously reported, conformationally defined, amphetamine analogs.