Dual M3 antagonists-PDE4 inhibitors. Part 2: Synthesis and SAR of 3-substituted azetidinyl derivatives

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 11, 2007, Pages 3077-3080

  Provins, Laurent ^a   Christophe, Bernard ^a   Danhaive, Pierre ^a   Dulieu, Jacques ^a   Gillard, Michel ^a   Quéré, Luc ^a   Stebbins, Karin ^a  

^a UCB PHARMA   (Belgium)

Author keywords

Azetidine; COPD; Muscarinic receptor(s); Phosphodiesterase; Pyrimidine

Indexed keywords

4,6 PYRIMIDINEDIAMINE DERIVATIVE; AZETIDINYL DERIVATIVE; MUSCARINIC M3 RECEPTOR ANTAGONIST; PHOSPHODIESTERASE IV INHIBITOR; UCB 101333 3; UNCLASSIFIED DRUG; 3',5' CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; AZETIDINE DERIVATIVE; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 4; MUSCARINIC M3 RECEPTOR; PYRIMIDINE DERIVATIVE;

ARTICLE; DRUG ACTIVITY; DRUG SYNTHESIS; IN VIVO STUDY; STRUCTURE ACTIVITY RELATION; ANIMAL; BAGG ALBINO MOUSE; CHEMISTRY; DRUG ANTAGONISM; FEMALE; GUINEA PIG; HUMAN; MOUSE; SYNTHESIS;

3',5'-CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; ANIMALS; AZETIDINES; FEMALE; GUINEA PIGS; HUMANS; MICE; MICE, INBRED BALB C; PYRIMIDINES; RECEPTOR, MUSCARINIC M3; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 34247892403     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.03.047     Document Type: Article

References (9)

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2. 3H]cAMP as a substrate. Data shown in tables are average results of two independent experiments.
3. 3H]N-methylscopolamine performed in CHO cell membranes expressing recombinant human receptors. Data shown in tables are average results of 2 independent experiments.
4. All titrations were performed using a GlpKa™ (Sirius, Forest Row, UK) and done in aqueous solution or methanol-water mixture with 0.15 M KCl at 25 °C using standardized 0.5 M HCl titrant.
5. Christophe B., Lelubre F., Provins L., Peck M., and Massingham R. The Pharmacologist 44 (2002) A227
6. 2O and osmolarity restored with 100 μl 2× HBSS (-/-). The cells were centrifuged again and the pellet was resuspended in 150 μl 0.1% BSA/HBSS. Total cells recovered are determined using a Coulter counter. Cytospin slides were prepared for differential cell count determination. Slides were stained with 3-step stain for differential counting, and 300 cells were counted per slide. Supernatant KC was analyzed by ELISA (R&D Systems) following manufacturer's instructions. The compounds were prepared in saline as a vehicle.
7. Stebbins K.J., Provins L., and Ellis J.L. Am. J. Respir. Crit. Care Med. 167 (2003) A486
8. Fiévez L., Kirschvink L., Onclinx C., Belleflamme M., Provins L., and Gustin P. Eur. Respir. J. 26 Suppl. 49 (2005) 579s
9. Kirschvink N., Fiévez N., Marlin D., Smith N., Provins L., and Gustin P. Eur. Respir. J. 26 Suppl. 49 (2005) 104s