Discovery and Structure−Activity Relationship of N-(Ureidoalkyl)-Benzyl-Piperidines As Potent Small Molecule CC Chemokine Receptor-3 (CCR3) Antagonists

Abstract

Structure-activity relationship (SAR) studies of initial screening hits from our corporate library of compounds and a structurally related series of CCR1 receptor antagonists were used to determine that an N-(alkyl)benzylpiperidine is an essential pharmacophore for selective CCR3 antagonists. Further SAR studies that introduced N-(ureidoalkyl) substituents improved the binding potency of these compounds from the micromolar to the low nanomolar range. This new series of compounds also displays highly potent, in vitro functional CCR3-mediated antagonism of eotaxin-induced Ca(2+) mobilization and chemotaxis of human eosinophils.

Small molecule antagonists for chemokine CCR3 receptors

“…In compounds 24a-e (Table VI), 55 the linker between the urea and the piperidine ring consists of a phenyl group directly attached to the urea and coupled to the piperidine via an alkyl group at its o-position. The optimal length of this alkyl group was reported to be two atoms (n 5 2), with n 5 1 giving reduced CCR3 affinity (compare 24a and 24b) and n 5 0 an even higher IC 50 value (data not shown).…”

Synthesis and Antiproliferative Activitiy of Novel Diaryl Ureas Possessing a 4H‐Pyrido[1,2‐a]pyrimidin‐4‐one Group

“…Subsequently, the intermediate 2 underwent reduction with Fe in ethanol to produce compound 3 [8]. The target compounds 4a -4f were synthesized from 3 with a variety of substituted arylisocyanates [9]. The new compounds 8a -8g were prepared successfully according to the same method as described for 4a -4f when the initial material was replaced with pyridin-2-amine (Scheme 1).…”

“…2-(4-Nitrophenyl)acetic acid was refluxed in ethanol with 0.15 equivalents of 98% sulfuric acid to afford compound 9 in good yield [10], which was then treated with DMF/DMA to give 10 [11]. The cyclization of 10 with pyridine-2-amine was carried out in acetic acid to obtain the intermediate 11 [12,13] to give compound 12 [8], which was reacted with substituted arylisocyanate to afford the target compounds 13a -13g [9]. In addition, the intermediates 14a -14g were prepared from substituted anilines with bis(trichloromethyl)carbonate (BTC) in ethyl acetate or 1,4-dioxane at 808C [14] (Scheme 3).…”

Identification and Characterization of Novel Antagonists of the CCR3 Receptor

“…6,11,12 In recent years, several new classes of CCR3 antagonists that were active in eosinophil chemotaxis assays have been discovered by different research groups. [13][14][15][16][17] Information on the in vivo activity of these compounds has yet to be published.…”