Design and synthesis of xanthine analogues as potent and selective PDE5 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 12, Issue 21, 2002, Pages 3149-3152

  Wang, Yuguang ^a   Chackalamannil, Samuel ^a   Hu, Zhiyong ^a   Boyle, Craig D ^a   Lankin, Claire M ^a   Xia, Yan ^a   Xu, Ruo ^a   Asberom, Theodros ^a   Pissarnitski, Dmitri ^a   Stamford, Andrew W ^a   Greenlee, William J ^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  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

PHOSPHODIESTERASE INHIBITOR; PHOSPHODIESTERASE V INHIBITOR; SILDENAFIL; UNCLASSIFIED DRUG; XANTHINE DERIVATIVE;

ALKYLATION; ANIMAL EXPERIMENT; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; CHEMICAL MODIFICATION; CONTROLLED STUDY; CORPUS CAVERNOSUM; DRUG ABSORPTION; DRUG CLEARANCE; DRUG DESIGN; DRUG EFFECT; DRUG EFFICACY; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; IC 50; MALE; NONHUMAN; SMOOTH MUSCLE RELAXATION; STRUCTURE ACTIVITY RELATION;

3',5'-CYCLIC-GMP PHOSPHODIESTERASE; ALKYLATION; ANIMALS; AREA UNDER CURVE; DRUG DESIGN; ELECTRIC STIMULATION; MALE; MUSCLE CONTRACTION; MUSCLE RELAXATION; PENIS; PHOSPHODIESTERASE INHIBITORS; PHOSPHORIC DIESTER HYDROLASES; PIPERAZINES; RABBITS; STRUCTURE-ACTIVITY RELATIONSHIP; XANTHINES;

EID: 18644364684     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(02)00646-7     Document Type: Article

References (9)

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5. All of the target compounds were purified by preparative TLC and showed satisfactory results in the analysis by NMR, MS and HRMS.
6. Human PDEs 5 and 2 isolated from corpus cavernosum and PDE3 isolated from platelets were assayed as described previously (Wang, P.; Wu, P.; Myers, J. G.; Stamford, A.; Egan, R. W.; Billah, M. M. Life Sci. 2001, 68, 1997). Recombinant human PDE1A3 was assayed at the final concentration of cAMP of 10 μM. Recombinant human PDE1A3 was assayed at the final concentration of cAMP of 10 μM. Recombinant human PDE4B2 was assayed at the final concentration of cAMP of 1 μM. Human PDE6 isolated from retina was assayed at the final concentration of cGMP of 0.5μM. All the PDE assays were performed in the presence of 2% DMSO and 0.1% BSA. All the assays were done in duplicate, and data shown are means from 2-4 experiments (SEM <15%).
7. 3: 412.2349, found: 412.2332.
8. The corpus cavernosum from anesthetized male New Zealand rabbits was mounted in organ bath chambers containing physiological salt solution. The optimum length-tension curves were obtained by gradual stretching and contracting the tissues with phenylephrine 10 μM. The tissues were equilibrated in a solution containing atropine (1 μM), guanethideine (5 μM) and indomethacin (5 μM). After the tissues were equilibrated, they were subjected to electrical field stimulation (10 V, 0.5 ms pulse duration) at 0.5-16 Hz. The tissues were then incubated with vehicle, or test compound (30 nM) for 30 min contracted with phenylephrine. The electrical stimulation was repeated. Relaxation was calculated as a percentage of phenylephrine-induced contraction. For details, see: Vemulapalli, S.; Kurowski, S. Fundamental & Clinical Pharmacol. 2001, 15, 1.
9. Compound 25 was formulated in PG/TW80 due to its low water solubility. For the reference of the rapid rat assay, see: Cox K.A., Dunn-Meynell K., Korfmacher W.A., Broske L., Nomeir A.A., Lin C.C., Cayen M.N., Barr W.H.A. Drug Discov. Today. 4:1999;232.