Nonpeptide angiotensin II antagonists: N-phenyl-1H-pyrrole derivatives are angiotensin II receptor antagonists

Abstract

A series of 5-[1-[4-[(4,5-disubstituted-1H-imidazol-1-yl)methyl]- substituted]-1H-pyrrol-2-yl]-1H-tetrazoles and 5-[1-[4-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-substituted]- 1H-pyrrol-2-yl]-1H-tetrazoles were investigated as novel AT1-selective angiotensin II receptor antagonists. Computer-assisted modeling techniques were used to evaluate structural parameters in comparison to the related biphenyl system. New synthetic procedures have been developed to prepare the novel compounds. The best antagonists in this series had IC50 values (rat uterine membrane receptor binding) in the 10(-8) M range and corresponding pA2 in isolated organ assay (rabbit aorta rings). Structure-activity relationships indicate some similarities with the finding in the biphenyl system. Substitution on the pyrrole ring modulates activity. Compound 5 antagonized angiotensin-induced blood pressure increase when administered to conscious rat at 30 mg/kg per os.

A 3D QSAR CoMFA study of non-peptide angiotensin II receptor antagonists

“…By D-optimal design, 18 out of the original 28 compounds were selected. The 10 leftover molecules are compounds 2, 12, 15,17,18,21,22,24,25 and 28, which could be used as an external set, although we fully agree that this would be a biased set and anyway not a real test set.…”

Spectroscopic Studies of Newly Synthesized Steroidal Pyrroles

“…After the completion of the reaction, excess solvent was removed to three-fourths of the original volume under reduced pressure. The reaction mixture was taken in diethyl ether (15 …”

“…2 The biological importance of pyrrole and its derivatives cannot be overemphasized because they have shown to possess extensive biological activities and pharmacological properties such as antimicrobial, analgesics, ionotropic, antitumor, anti-inflammatory, and antiallergic. [3][4][5][6][7][8][9][10] These have also been employed as P38kinase, 11 prolyl -4-hydroxylase, 12 poly(ADP-ribose) polymerase inhibitors, 13 estrogen receptor β-selective ligands, 14 AT1-selective angiotensin II receptor antagonists, 15 and minor groove recognition elements. 16 Several macromolecular antibiotics having pyrrole structure were isolated from biological sources, and their activities were defined.…”

Practical one-pot sequential procedure for the preparation of N-arylated 3,4-disubstituted pyrroles from alkenes

“…N-Arylated substituted pyrroles have been found very important applications in pharmaceutical researches [1][2][3][4][5][6][7][8][9][10][11][12][13]. Paal-Knorr pyrrole synthesis offered a classic route for their preparation, but with limitation by using pre-formed 1,4-diketones [8][9][10][11][12][13].…”

“…Paal-Knorr pyrrole synthesis offered a classic route for their preparation, but with limitation by using pre-formed 1,4-diketones [8][9][10][11][12][13]. Recently, many alternative synthetic methods have been developed for this purpose.…”