Optimization of purine based PDE1/PDE5 inhibitors to a potent and selective PDE5 inhibitor for the treatment of male ED

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 9, 2005, Pages 2365-2369

  Boyle, Craig D ^a   Xu, Ruo ^a   Asberom, Theodros ^a   Chackalamannil, Samuel ^a   Clader, John W ^a   Greenlee, William J ^a   Guzik, Henry ^a   Hu, Yuequing ^a   Hu, Zhiyong ^a   Lankin, Claire M ^a   Pissarnitski, Dmitri A ^a   Stamford, Andrew W ^a   Wang, Yuguang ^a   Skell, Jeffrey ^a   Kurowski, Stanley ^a   Vemulapalli, Subbarao ^a   Palamanda, Jairam ^a   Chintala, Madhu ^a   Wu, Ping ^a   Myers, Joyce ^a   Wang, Peng ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Erectile dysfunction; Male ED; PDE5 inhibitor; Purine

Indexed keywords

ISOENZYME; PHOSPHODIESTERASE I INHIBITOR; PHOSPHODIESTERASE INHIBITOR; PHOSPHODIESTERASE V INHIBITOR; PURINE DERIVATIVE; SILDENAFIL; TADALAFIL; UNCLASSIFIED DRUG; VARDENAFIL;

ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG ACTIVITY; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME INHIBITION; ERECTILE DYSFUNCTION; IN VIVO STUDY; NONHUMAN; STRUCTURE ACTIVITY RELATION;

EID: 20244382999     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.02.083     Document Type: Article

References (17)

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8. 50 values reported for compounds 1 and 2 are different in this paper than the published values in Ref. 7
9. See Ref. 7 for the synthesis of imidazole I
10. The (R)-configuration at C-7 was preferred for PDE5 inhibition. For example the (S)-enantiomers of compounds 6 and 10 had PDE5 inhibition of 11% and 12% @ 100 nM, respectively
11. Imidazole VI was synthesized with the same chemistry used to produce imidazole I (Ref. 7). Triethylorthoformate was used for the formation of VI in place of the triethylorthoacetate employed for the synthesis of I
12. 2 (PDE9) and 0.7 μM cGMP (PDE10)
13. Rats were orally dosed (0.4% w/v methyl cellulose) with compound 41 at 10 mg/kg. Plasma levels were sampled for 24 h (n = 2)
14. Sildenafil PK in rat was measured using the same conditions as Ref. 13
15. Dogs were orally dosed (0.4% w/v methyl cellulose) with compound 41 at 5 mg/kg. Plasma levels were sampled for 4 h (n = 3)
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