Urinary incontinence is a condition defined as the involuntary loss of urine and was recently classified as a disease by the World Health Organization. Involuntary loss of urine occurs when pressure inside the bladder exceeds the retentive pressure of the urethral sphincters (intraurethral pressure). The disease may arise from different pathological, anatomical and neurological factors. Three major types of urinary incontinence have been defined based on symptoms, signs and condition: stress, urge and mixed incontinence.
Stress urinary incontinence (SUI) is the involuntary loss of urine during coughing, sneezing, laughing, or other physical activities that increase intra-abdominal pressure in the absence of a bladder contraction. SUI is most common in women between the ages of 25 and 50, and up to 47% of regularly exercising women have some degree of SUI.
The most common causes of SUI in women are urethral hypermobility and intrinsic urethral sphincter deficiency. Urethral hypermobility is characterized by a weakness of the pelvic floor support. Because of this weakness, there is rotational descent of the bladder neck and proximal urethra during increases in abdominal pressure. If the urethra opens concomitantly, SUI may ensue. Intrinsic urethral sphincteric deficiency denotes a dysfunction of the urethral smooth and striated muscle support system. This may have congenital origins, or may be acquired after surgery, trauma, or a sacral cord lesion. In females, intrinsic urethral sphincter deficiency is commonly associated with multiple incontinence surgical procedures, as well as hypoestrogenism, aging or both. In this condition, the urethral smooth muscle and sphincter is unable to generate enough resistance to retain urine in the bladder, especially during the stress maneuvers. It is believed that a number of patients suffer from both urethral hypermobility and intrinsic urethral sphincter deficiency.
The present methods to treat SUI include physiotherapy and surgery. Treatment with pharmaceutical agents is limited to the use of non-selective adrenergic agonists like phenylpropanolamine and midodrine. The rationale for the use of adrenergic agonists for the treatment of SUI is based on physiological data indicating an abundant noradrenergic input to smooth muscle of the urethra. Studies in rats, cats and dogs indicate that sympathetic adrenergic input to the urethra is tonically active during bladder filling to promote urine storage, and that surgical or pharmacological blockade of the sympathetic pathways can reduce urethral resistance.
Substantial preclinical physiological, pharmacological and molecular evidence suggests that .alpha..sub.1A adrenoceptors are responsible for mediating the effects of norepinephrine on urethral tone. Receptor binding and autoradiographic studies have revealed the existence of .alpha..sub.1 adrenoceptors in human, rabbit and dog urethra (Chapple C, Aubry M, James S, Greengrass P, Burnstock G, Turner-Warwick R, Milroy E and Davey M (1989). Characterisation of human prostatic adrenoceptors using pharmacology receptor binding and localization. British Journal of Urology 63: 487-496; Testa R, Guarnieri L, Ibba M, Strada G, Pogessi E, Taddei C, Simonazzi I and Leonardi A (1993). Characterization of alpha-1 adrenoceptor subtypes in prostate and prostatic urethra of rat, rabbit dog and man.
European Journal of Pharmacology 249: 307-315; Nishi K, Latifpour J, Saito M, Foster H, Yoshida M and Weiss R (1998). Characterization, localization and distribution of .alpha.1 adrenoceptor subtype in male rabbit urethra. Journal of Urology 160: 196-205), and in vitro studies demonstrated that the cc, receptors regulate urethral tone as phenylephrine can contract isolated urethral strips from several animal species (Bridgewater M, MacNeil H and Brading A (1993). Regulation of tone in pig urethral smooth muscle. Journal of Urology 150: 223-228; Chess-Williams R, Aston N and Couldwell C (1994). .alpha.1 A-adrenoceptor subtype mediates contraction of the rat urethra. Journal Autonomic Pharmacology 14: 375-381). Isolated strips of human urethral muscle also contract in response to .alpha..sub.1 adrenoceptor agonists, a response that is blocked by .alpha..sub.1 antagonists like prazosin (Brading A, Fry C, Maggi C, Takeda M, Wammack R, Wicklund N, Uvelius B and Gabella G (1998). Incontinence: Cellular Biology. In: Incontinence (Eds. Abrams P, Khoury S and Wein A), pp. 59-104, Monaco; Chapple 1989). Similarly, systemic injections of epinephrine increase intraurethral pressure in anesthetized dogs, an effect also blocked by prazosin (Sommers W, Felsen D, Chou T, Marion D, Chernesky C and Darracott-Vaughan E (1989). An in vivo evaluation of alpha adrenergic receptors in canine prostate. Journal of Urology 141: 1230-1233).
Adrenoceptors are cell membrane receptors belonging to the heptahelical G-protein family of receptors (GPCRs) that respond to the physiological agonists, norepinephrine and epinephrine (Hancock A (1996). .alpha.1 adrenoceptor subtypes: A synopsis of their pharmacology and molecular biology. Drug Development Research 39: 54-107). They are divided into 3 families: .alpha..sub.1, .alpha..sub.2 and .beta.. Although .alpha. adrenoceptors were originally subclassified into ".alpha..sub.1 postsynaptic" and ".alpha..sub.2 presynaptic", this purely anatomical classification was later abandoned and defined based on the pharmacology and the molecular biology of the cloned receptors (Langer S (1999). History and nomenclature of .alpha.1-adrenoceptors. European Urology 36: 2-6). Six genes have been identified and sequenced to support the present classification: .alpha..sub.1a, .alpha..sub.1b, .alpha..sub.1d, .alpha..sub.2b, and .alpha..sub.2c (as recommended by IUPHAR, lowercase subscripts designate the cloned subtypes, and uppercase subscripts define the pharmacologically defined subtypes). The elucidation of the molecular diversity of adrenoceptors has provided a molecular correlate to earlier pharmacological studies. The use of subtype specific probes has shown that the human, dog and rabbit urethra are enriched with mRNA for the .alpha..sub.1A adrenoceptor, and RNAase protection assays indicated that the .alpha..sub.1a subtype is the predominant subtype in human urethra.
Clinical studies with the non-selective a adrenoceptor agonists, PPA and midodrine have demonstrated limited clinical efficacy. The use of PPA has been limited by concerns regarding dose-limiting side effects, particularly hypertension, that have curtailed the ability to evaluate the compound at higher doses. PPA is a non-selective adrenergic agonist lacking selectivity for .alpha..sub.1, adrenoceptors in tissue bath studies. Several patents like EP 887,346; EP 538,469 and U.S. Pat. No. 5,610,174 disclose compounds that are claimed as selective .alpha..sub.1A adrenoceptor agonists.
Adrenergic receptors in the vascular bed regulating blood pressure are presumed to be mainly of the .alpha..sub.1B subtype. Adrenergic antagonists (like prazosin and terazosin) reduce blood pressure in Spontaneously Hypertensive rats (SHRs) with a potency ranking that correlates with their potency to displace binding to the .alpha..sub.1b receptor but not the .alpha..sub.1a receptor (Hancock 1996), and a reduced hypertensive response to phenypephrine has been observed in .alpha..sub.1b knock-out mice (Cavalli A, Lattion A, Hummler E, Nonniger M, Pedrazzini T. Aubert J, Michel M, Yang M, Lembo G, Vecchione C, Mostardini M, Schmidt A, Beerman F and Cotecchia S (1997). Decreased blood pressure response in mice deficient of the .alpha.1-adrenergic receptor. Proceedings of the National Academy of Sciences USA 94:11589-11594). However, there is recent data to suggest that .alpha..sub.1A receptors may also exist extra-synaptically in the vasculature, and while such receptors may not be involved in the normal regulation of blood pressure they may respond to exogenous .alpha..sub.1A agonists. Based on these data, the .alpha..sub.1B antagonist attributes may reduce the hypertensive liability of the .alpha..sub.1A adrenergic agonists.
The .alpha..sub.1 receptors in the bladder are mainly the .alpha..sub.1D subtype. Adrenergic antagonists like prazosin decrease bladder hyperreflexia and increase bladder capacity (Andersson K (1999). .alpha.1-adrenoceptors and bladder function. European Urology 36: 96-102). In view of these clinical findings, .alpha..sub.1D antagonism may provide additional benefit to patients with mixed incontinence.
There continues to be a need for medicaments that are useful for treating incontinence. A compound having the desired .alpha..sub.1A agonist and .alpha..sub.1B and preferably .alpha..sub.1D antagonist profile may be useful in treating incontinence.