Discovery of a potent, selective and orally bioavailable 3,9-diazaspiro[5.5]undeca-2-one CCR5 antagonist

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 1, 2009, Pages 209-213

  Yang, Hanbiao ^a   Lin, Xiao Fa ^a   Padilla, Fernando ^a   Gabriel, Stephen D ^a   Heilek, Gabrielle ^a   Ji, Changhua ^a   Sankuratri, Surya ^a   deRosier, André ^a   Berry, Pamela ^a   Rotstein, David M ^a  

^a ROCHE BIOSCIENCE   (United States)

Author keywords

3,9 Diazaspiro 5.5 undecan 2 one; 3,9 Diazaspiro 5.5 undecane; Anti HIV 1; CCR5 antagonist

Indexed keywords

3,9 DIAZASPIRO[5.5]UNDECA 2 ONE DERIVATIVE; 3,9 DIAZASPIRO[5.5]UNDECANE DERIVATIVE; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; ARTICLE; ASYMMETRIC SYNTHESIS; DRUG BIOAVAILABILITY; DRUG HALF LIFE; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; HUMAN; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ALKANES; ANIMALS; ANTIVIRAL AGENTS; BIOLOGICAL AVAILABILITY; DRUG DISCOVERY; RECEPTORS, CCR5; SPIRO COMPOUNDS; STRUCTURE-ACTIVITY RELATIONSHIP;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 57749104798     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.10.115     Document Type: Article

References (14)

1. Perno C.-F., Moyle G., Tsoukas C., Ratanasuwan W., Gatell J., and Schechter M. J. Med. Virol. 80 (2008) 565
2. For reviews, see:. Repik A., Richard K.H., and Clapham P.R. Curr. Opin. Investig. Drugs 8 (2007) 130
3. Palani A., and Tagat J. J. Med. Chem. 49 (2006) 2851
4. Kazmierski W., Bifulco N., Yang H., Boon L., DeAnda F., Watson C., and Kenakin T. Bioorg. Med. Chem. Lett. 11 (2003) 2663 and references therein
5. For recent publications, see:. Ernst J., Dahl R., Lum C., Sebo L., Urban J., Miller S.G., and Lundström J. Bioorg. Med. Chem. Lett. 18 (2008) 1498
6. Thoma G., Beerli C., Bigaud M., Bruns C., Cooke N.G., Streiff M.B., and Zerwes H.-G. Bioorg. Med. Chem. Lett. 18 (2008) 2000 and references therein
7. For a patent application, see: Gabriel, S. D.; Rotstein, D. M. US 2005176703 A1, 2005; Chem. Abstr. 2005, 143, 211895.
8. Yang H., Lin X.-F., Padilla F., and Rotstein D.M. Tetrahedron Lett. 49 (2008) 6371
9. Ji C., Zhang J., Cammack N., and Sankuratri S. J. Biomol. Screen. 11 (2006) 65
10. 50 from cell-cell fusion assay will be used. For a similar observation, see Ref. 3a.
11. Kondru R., Zhang J., Ji C., Mirzadegan T., Rotstein D., Sankuratri S., and Dioszegi M. Mol. Pharmacol. 73 (2008) 289
12. Walker D., Abel S., Comby P., Muirhead G., Nedderman A., and Smith D. Drug Metab. Dispos. 33 (2005) 587
13. For an asymmetric synthesis of 43, see Ref. 5.
14. Chiral HPLC condition: chiralpak AD column, 95/5 hexane/EtOH as solvent at 1.4 mL/min. Compound 44 has a retention time of 9.29 min.