Agent for the prevention and treatment of prostatic hyperplasia comprising pyrazolopyrimidinone compound
Inventors
YU, Jae Young • Choi, Seul Min • Kang, Kyung Koo • Ahn, Byoung Ok • Yoo, Moohi
Assignees
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Publication Number
US-8148386-B2
Publication Date
2012-04-03
Expiration Date
Abstract
The present invention relates to an agent for preventing and treating benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) associated with BPH and a relaxant for relaxing urethral smooth muscle or prostatic smooth muscle comprising a pyrazolopyrimidinone compound as an effective ingredient. The agent in accordance with the present invention can provide nitric oxides by inhibiting the activity of PDE-5 that decomposes c-GMP, and the provided nitric oxides relax the urethral smooth muscle or the prostatic smooth muscle to lower the intraurethral pressure (IUP), thus treating BPH and LUTS associated with BPH. Furthermore, the time required for reaching a maximum blood concentration is shorter and the half-life is longer than the other PDE-5 inhibitors, thus reducing the frequency of administration. Moreover, the agent of the invention causing few side effects can be efficiently used as a safe drug.
Core Innovation
The disclosure provides an agent for preventing and treating benign prostatic hyperplasia (BPH) and BPH-associated lower urinary tract symptoms (LUTS) by administering a compound of Formula 1. The compound is a pyrazolopyrimidinone PDE-5 inhibitor that increases NO/cGMP signaling through inhibition of PDE-5 to promote relaxation of urethral smooth muscle and prostatic smooth muscle and to lower intraurethral pressure.
The disclosure states that the compound of Formula 1 shows improved pharmacokinetics compared with other PDE-5 inhibitors, including a shorter time to maximum blood concentration (Cmax) and a longer half-life of 9–15 hours. It further states that these pharmacokinetic properties enable reduced dosing frequency and limited drug accumulation, and that urogenital tissue affinity is characterized by slower decline in organ concentrations compared with sildenafil.
The disclosure also states that reduced side-effect risk is attributed to a lack of PDE-11 inhibition, including no testicle toxicity and no myalgia, and it further attributes reduced risk to reduced liver metabolism and reduced inhibitor interactions. The disclosure describes rat models of BPH-driven increases in intraurethral pressure showing dose-dependent inhibition and includes organ distribution data and human pharmacokinetics data showing a longer half-life than sildenafil.
Claims Coverage
The document includes one independent method claim. Across the dependent claims, the inventive concept is centered on using the Formula 1 compound to treat BPH or a BPH-associated symptom, with refinements covering specific BPH-associated symptom scope, smooth-muscle relaxation and intraurethral pressure effects, PDE-5 inhibition with non-inhibition of PDE-11, and specified pharmacokinetic timing and half-life constraints.
Treating BPH with Formula 1 compound administration
A method for treating benign prostatic hyperplasia (BPH) or a BPH associated symptom comprising administering an effective amount of a compound of Formula 1 to a subject in need thereof.
LUTS as the BPH-associated symptom
The BPH associated symptom is lower urinary tract symptom (LUTS).
Relaxing urethral and prostatic smooth muscle
The compound of Formula 1 relaxes prostatic smooth muscle or urethral smooth muscle.
PDE-5 inhibition without PDE-11 inhibition
The compound of Formula 1 does not inhibit PDE-11 activity but does inhibit PDE-5 activity.
Reaching maximum blood concentration within 50 to 70 minutes
The maximum blood concentration of the compound of Formula 1 is reached within 50 to 70 minutes.
Overall claim coverage is directed to administering an effective amount of a Formula 1 pyrazolopyrimidinone PDE-5 inhibitor to treat BPH or BPH-associated LUTS, with emphasis on relaxing urethral/prostatic smooth muscle, lowering intraurethral pressure, maintaining PDE-5 inhibition while not inhibiting PDE-11, and achieving specified pharmacokinetic timing and duration characteristics (including a stated 9–15 hour half-life in dependent refinements).
Stated Advantages
Improved pharmacokinetics versus other PDE-5 inhibitors, including shorter time to Cmax and a longer half-life of 9–15 hours.
Reduced dosing frequency and limited drug accumulation.
Higher urogenital tissue affinity characterized by slower decline in organ concentrations.
Reduced side-effect risk attributed to lack of PDE-11 inhibition, including no testicle toxicity and no myalgia.
Reduced risk attributed to reduced liver metabolism and reduced inhibitor interactions.
Lower intraurethral pressure by relaxing urethral and prostatic smooth muscle.
Documented Applications
Treatment of benign prostatic hyperplasia (BPH) and BPH-associated lower urinary tract symptoms (LUTS) by administering a Formula 1 compound to a subject in need.
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