Discovery of the First Non-Peptide Full Agonists for the Human Bradykinin B₂Receptor Incorporating 4-(2-Picolyloxy)quinoline and 1-(2-Picolyl)benzimidazole Frameworks

Abstract

In the course of our studies on non-peptide bradykinin (BK) B(2) receptor ligands, it was suggested that the 4-substituent of the quinoline ring may play a critical role in determining binding affinities for human and guinea pig B(2) receptors, as well as agonist/antagonist properties. We carried out an extensive investigation to elucidate the structure-activity relationships (SAR) for this key pharmacophore. Introduction of lower alkoxy groups to the 4-position of the quinoline ring of 3 led to the identification of 4-ethoxy derivative 22b as a unique partial agonist. This compound significantly stimulated inositol phosphates (IPs) formation in Chinese hamster ovary cells expressing the cloned human B(2) receptor at concentrations greater than 10 nM and displayed one-tenth of the intrinsic activity of BK. The agonist activity of 22b was selective for the B(2) receptor and was inhibited by selective peptide and non-peptide B(2) antagonists. On the other hand, 22b strongly suppressed BK-induced IPs formation through the cloned human B(2) receptor. Further studies on the key pharmacophore led to identification of a 2-picolyloxy moiety as a powerful agonist switch, leading to the discovery of a potent and efficacious non-peptide B(2) agonist, 19a. Successive optimization of the acyl side chain afforded 38, which exhibited full agonist activity on stimulation of IPs formation. Furthermore, this strategy could be applied successfully to the benzimidazole series. The representative 1-(2-picolyl)benzimidazole derivative 47c increased PGE(2) production at a 1 microM concentration to the same level as the maximum effect of BK. Thus, we have established the medicinal chemistry modifications required to convert our highly potent non-peptide B(2) antagonists to agonists with potent efficacy.

Synthesis and Characterization of Antimicrobial Activity of Quinoline Derivatives

“…Chemistry of Quinoline derivatives has been of increasing Quinoline family compounds are widely used as a parent compound to make drugs, fungicides, biocides, alkaloids, dyes, rubber, chemicals, flavoring agents, antiseptic. [1] Quinoline derivatives have been reported anti-inflammatory [2] , antibacterial [3,4,5] , antifungal [6,7] , antiallergy [8] , antidepressant [9] , antiasthmatic [10] , antimalarial [11][12][13] , antiviral [14,15] , antitumour [16] , neuroleptic activity [17] , antihypertensive [18,19] , cytotoxic [20][21][22] , antihistamine [23] , CVS [24] , antiseptic, analgesic, antihelmintic [25] , hypnotic, sedative and CNS [26] , Bronchodilator activities [27] The present work we have attempted to combine the 3-formyl-6-nitroquinoline-2-thione with various aryl amines to get some novel 3-formyl-6-nitroquinoline-2-thionederivatives and screened for their possible anti-oxidant and wound healing properties.…”

Carbon-Based Solid Acid Catalyzed Synthesis of Polyhydroquinoline Derivatives via Hantzsch Reaction Under Solvent-Free Conditions

“…In recent years, much attention has been devoted to the synthesis of polyhydroquinoline compounds due to their diverse therapeutic and pharmacological properties, such as vasodilator, antitumor, bronchodilator, antiartherosclerotic, geroprotective and hepatoprotective activity [1][2][3][4][5][6] . Particularly, 4-aryl-1,4-dihydropyridines are well known as calcium channel blockers and have emerged as one of the most important class of drugs for the treatment of cardiovascular diseases 7 .…”

“…Recently, a number of improved methods have been reported in the literature for the synthesis of polyhydroquinolines which involve the use of microwave irradiation 12 , solar thermal energy 13 , grinding 14 , and also using various catalysts such as ionic liquid 15 , metal triflates 16 , HY-Zeolite 17 , montmorillonite K-10 18 , cerium(IV) ammonium nitrate 19 , HClO 4 -SiO 2 20 , molecular iodine 21 , Yb(OTf) 3 …”

Selective alkylation of aminophenols

“…They have been widely used in the synthesis of pharmaceutical agents, [1][2][3][4] such as non-peptide full agonists for the human bradykinin B 2 receptor 1 and cholesterol acyltransferase inhibitors, 2 and chiral ligands for asymmetric catalysis. 5,6 Both of alkoxyanilines and N-alkylaminophenols can be prepared from aminophenols via alkylation.…”