Synthesis and biological activities of novel β-carbolines as PDE5 inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 4, 2003, Pages 761-765

  Sui, Zhihua ^a   Guan, Jihua ^a   Macielag, Mark J ^a   Jiang, Weiqin ^a   Qiu, Yuhong ^a   Kraft, Patricia ^a   Bhattacharjee, Sheela ^a   John, T Matthew ^a   Craig, Elizabeth ^a   Haynes Johnson, Donna ^a   Clancy, Joanna ^a  

^a JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BETA CARBOLINE DERIVATIVE; PHOSPHODIESTERASE; PHOSPHODIESTERASE INHIBITOR; PHOSPHODIESTERASE V; SILDENAFIL; UNCLASSIFIED DRUG;

ARTICLE; DOG; DRUG EFFICACY; DRUG POTENCY; DRUG SELECTIVITY; DRUG SOLUBILITY; DRUG SYNTHESIS; ERECTILE DYSFUNCTION; HUMAN; IN VIVO STUDY; NONHUMAN; STRUCTURE ACTIVITY RELATION; VISUAL DISORDER;

CANIS FAMILIARIS;

EID: 0037294043     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(02)01036-3     Document Type: Article

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17. i values.
18. This study was adapted from Carter, A. J.; Ballard, S. A.; Naylor, A. M. J. Urol. 1998, 160, 212, with modifications. Male beagles were anesthetized and the anesthesia was maintained throughout the course of the experiment by pentobarbital infusion. Arterial blood pressure was monitored. The pelvic nerve was exposed and hooked to a bipolar electrode. Penis was denuded and a 19-gauge needle attached to a pressure transducer via a catheter was inserted into the corpus cavernosum to record intracavernosal pressure (ICP). Control ICP responses were generated by electrical stimulation to the pelvic nerve at appropriate current output and frequency setting that increased the ICP to about 30% of systolic pressure. After the control responses were established, ascending concentrations of test compound were given intravenously at 40-min intervals. The effect on ICP was evaluated at 15 min after each dosing by electrical stimulation to the pelvic nerve at the same setting. To determine the effect of the compound, the area under the curve (AUC) for ICP at each stimulation was computed and the control response AUC was subtracted. At the end of each experiment, 300 μg/kg sildenafil was given intravenously. This dose was shown to induce a maximal response in our hands and thus designated as 100%.