Discovery and structure–activity relationships of urea derivatives as potent and novel CCR3 antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 15; pp. 4951 - 4954
• Main Authors: Nitta, Aiko, Iura, Yosuke, Tomioka, Hiroki, Sato, Ippei, Morihira, Koichiro, Kubota, Hirokazu, Morokata, Tatsuaki, Takeuchi, Makoto, Ohta, Mitsuaki, Tsukamoto, Shin-ichi, Imaoka, Takayuki, Takahashi, Toshiya
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2012; Elsevier
• Subjects: Allergic diseases; antagonists; Biological and medical sciences; CCR3 antagonists; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Evaluation, Preclinical; Humans; Life Sciences & Biomedicine; Medical sciences; Naphthalenes - chemical synthesis; Naphthalenes - chemistry; Naphthalenes - metabolism; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Proline - chemistry; Proline moiety; Protein Binding; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - metabolism; Receptors, CCR3 - antagonists & inhibitors; Receptors, CCR3 - metabolism; Science & Technology; screening; Structure-Activity Relationship; structure-activity relationships; urea; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - metabolism; Urea derivatives; Urea derivatives; Allergic diseases; Proline moiety; CCR3 antagonists; Immunopathology; Allergy; Toxicity; Proline; CCR3 chemokine receptor; Urea; α-Aminoacid; Structure activity relation; Aminoacid; Ureas; Antagonist
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.06.042

The synthesis and structure–activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC50=190nM) derived from initial screening hit compound 1 (IC50=600nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC50=4.9nM) as a potent CCR3 antagonist.