A Novel Class of Orally Active Non-Peptide Bradykinin B₂ Receptor Antagonists. 3. Discovering Bioisosteres of the Imidazo[1,2-a]pyridine Moiety

Abstract

Recently we reported on overcoming the species difference of our first orally active non-peptide bradykinin (BK) B2 receptor antagonists, incorporating an 8-[[3-(N-acylglycyl-N-methylamino)-2, 6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridine skeleton, leading to identification of the first clinical candidate 4a (FR167344). With this potent new lead compound in hand, we then investigated further refinement of the basic framework by replacement of the imidazo[1,2-a]pyridine moiety and discovered several bioisosteric heterocycles. Extensive optimization of these new heteroaromatic derivatives revealed the detailed structure-activity relationships (SAR) around the imidazo[1, 2-a]pyridine ring and the 2,6-dichlorobenzyl moiety, leading to the discovery of our second clinical candidate 87b (FR173657) which inhibited the specific binding of [3H]BK to recombinant human B2 receptors expressed in Chinese hamster ovary (CHO) cells and guinea pig ileum membrane preparations expressing B2 receptors with IC50's of 1.4 and 0.46 nM, respectively. This compound also displayed excellent in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs with an ED50 value of 0.075 mg/kg by oral administration. Further modifications of the terminal substituents on the pyridine moiety led to a novel pharmacophore and resulted in the identification of 99 (FR184280), whose IC50 value for human B2 receptors (0.51 nM) was comparable to that of the second-generation peptide B2 antagonist Icatibant.

Enantiomerically Pure Hexahydropyrazinoquinolines as Potent and Selective Dopamine 3 Subtype Receptor Ligands

“…Briefly, quinolines 4, either commercially available or readily synthesized using published procedures, 22 were converted to quinoline-2-carboxylic acids 5 in two steps. 23 Coupling of the carboxylic acids 5 with (S)-R-methylbenzylamine yielded amides 6.…”

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

“…The benzyl alcohol 25 13 was treated with methanesulfonyl chloride followed by coupling with the quinolinol 9f. Removal of the N-phthaloyl group of 26 with hydrazine monohydrate and coupling with (E)-4-(substituted)cinnamic acids or (E)-3-[6-(substituted)-pyridin-3-yl]acrylic acids afforded the corresponding cinnamamides 28-33, 35, and 38.…”

Silica Sulfuric Acid as a Efficient and Recyclable Solid Acid Catalyst for the One-Pot Synthesis of 2,4,6-Triaylpyridines Under Solvent Free Conditions

“…Also, pyridines are very useful intermediates for the development of molecules of pharmaceutical and biological interest. Substituted pyridines derivatives have found applications in diverse therapeutic areas including anti-tuberculosis, anti-bacterial, antiinflammatory, anti-asthmatic, anti-depressant, and potent HIV protease inhibitor [3][4][5][6][7] . In addition to the pyridine ring is ubiquitous in agrochemicals such ORIENTAL JOURNAL OF CHEMISTRY 9 .…”