Author: Arias, L. ; Clarke, D. E. ; Romero, M. ; Morgans, D. J. ; Perez-Medrano, A. ; Padilla, F. ; Chan, R. ; Guzman, A. ; Quintero, C. ; Smith, S. A. ; Jasper, J. R. ; Blue, D. R. ; Lopez, F. J. ; Elworthy, T. R. ; Jaime-Figueroa, S. ; Ford, A. P. D. W. ; Williams, T. J. ; Sandoval, L.

Predominance in the urethra and prostate of the alpha(1A)-adrenoceptor subtype, which is believed to be the receptor mediating noradrenaline induced smooth muscle contraction in these tissues, led to the preparation of alpha(1A)-selective antagonists to be tested as uroselective compounds for the treatment of benign prostatic hyperplasia. Thus, a number of selective alpha(1A)-adrenoceptor antagonists were synthesized and assayed in vitro for potency and selectivity. Dog pharmacokinetic parameters of 12 (RO700004) and its metabolite 40 (RO1104253) were established. The relative selectivity of intravenously administered 12, 40 and standard prazosin to inhibit hypogastric nerve stimulation-induced increases in intraurethral prostatic pressure versus phenylephrine-induced increases in diastolic blood pressure in anesthetized dogs was 76, 71 and 0.6, respectively.

01 Jun 2001·International Journal of Impotence ResearchQ3 · MEDICINE

Evaluation of oral Ro70-0004/003, an α1A-adrenoceptor antagonist, in the treatment of male erectile dysfunction

Q3 · MEDICINE

Article

Author: D. R. Blue ; Trinity Bivalacqua ; A. Mokatrin ; D. Gennevois ; W. J G Hellstrom ; A. Choppin ; S. A. Mckinnon ; S. S. Hegde

Alpha-adrenoceptor antagonists have been used for the treatment of male erectile dysfunction (MED). Ro70-0004/003 (Ro70-0004) is a selective and orally active alpha1A-adrenoceptor antagonist. The objective of this study was to: (1) pharmacologically elucidate the alpha1-adrenoceptor subtype mediating norepinephrine-induced contraction of human isolated corpus cavernosal tissue and (2) conduct a clinical proof-of-concept study with Ro70-0004 to test the hypothesis that selective alpha1A-adrenoceptor blockade would improve erectile function in patients with MED. In vitro organ bath studies were conducted with strips of human isolated corpus cavernosal tissue obtained from patients undergoing penile prosthesis implantation. Prazosin, cyclazosin, RS-100329 and Ro70-0004/003 antagonized norepinephrine-induced contractile responses with affinity estimates (pK(B) or pA2) of 8.4, 7.3, 9.2 and 8.8, respectively, consistent with the singular involvement of alpha1A-adrenoceptor subtype. A clinical study (single center, observer-blind, randomized, placebo-controlled, extended period Latin-Square crossover design) was conducted in 24 male patients (mean age 44 y) with MED of no established organic cause to evaluate the efficacy of a 5-mg oral dose of Ro70-0004. The primary efficacy endpoint was the duration of rigidity > 60% at the base of the penis measured between 0.5 and 2.5 h post-dose. Rigidity was assessed by penile plethysmography using the RigiScan Plus device during visual sexual stimulation. The safety and efficacy of Ro70-0004 was also assessed. A 50-mg dose of sildenafil was included as a positive control. For the primary efficacy endpoint, the mean duration of erection was 9.69 min following administration of placebo, 8.28 min following Ro70-0004, and 22.64 min following sildenafil. Only the difference between sildenafil and placebo reached statistical significance (P < 0.05). A similar pattern was observed when measuring a duration of rigidity > 80% at the base of the penis (secondary endpoint). Ro70-0004 was safe and generally well tolerated (only two out of 20 patients reported at least one adverse event). The highly selective alpha1A-adrenoceptor antagonist, Ro70-0004, given at a single dose of 5 mg, did not improve erectile function when compared to placebo.

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Indication	Highest Phase	Country/Location	Organization	Date
Erectile Dysfunction	Phase 2	US	Roche Palo Alto LLC	-
Prostatic Hyperplasia	Phase 2	-	F. Hoffmann-La Roche Ltd.	-
Prostatic Hyperplasia	Phase 2	US	Roche Palo Alto LLC	-

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