title: Structure activity relationships of fused bicyclic and urea derivatives of spirocyclic compounds as potent CCR1 antagonists.
abstract: A series of fused bicyclic and urea derivatives of spirocyclic compounds were designed, synthesised and evaluated in vitro as potent CCR1 antagonists. In particular, 4 (7nM), 44 (1.3nM), 48 (0.89nM) and 50 (0.63nM) were the most potent hCCR1 antagonists in this series of compounds. Moreover, some of these substances demonstrated good rodent cross-over, especially 46 which exhibited very high rat CCR1 binding affinity with an IC50 value of 16nM.
authors: Department of Medicinal Chemistry, Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. Electronic address: nafizal.hossain@astrazeneca.com.
authors: Nafizal
authors: N
authors: Hossain
authors: Department of Medicinal Chemistry, AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors: Marguérite
authors: M
authors: Mensonides-Harsema
authors: Department of Medicinal Chemistry, Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors: Martin E
authors: ME
authors: Cooper
authors: Department of Medicinal Chemistry, AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors: Tomas
authors: T
authors: Eriksson
authors: Department of Medicinal Chemistry, AstraZeneca R&D Lund, Scheelevägen 1, SE-221 87 Lund, Sweden.
authors: Svetlana
authors: S
authors: Ivanova
authors: Department of Medicinal Chemistry, Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca R&D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors: Lena
authors: L
authors: Bergström
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D051381:Rats; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry*
chemical_list: D001643:Bridged Bicyclo Compounds; C515300:CCR1 protein, human; D054389:Receptors, CCR1; D013141:Spiro Compounds; D014508:Urea
keywords: Antagonists; CCR1; Chemokines; Receptor; Spirocyclic