Mark G. Bock and Michael A. Patane Merck Research Laboratories, West Point, PA 19486
Introduction - Benign prostatic hyperplasia (BPH) is a pathological disorder in men that develops in response to the action of dihydrotestosterone on the aging prostate gland (1-3). It is a disease that causes voiding difficulties and interferes with the perception of well-being. Although not fully defined, the origin of symptoms in men with BPH appears to result from a combination of two components: static or mechanical constriction of the urethra attributable to increased prostatic mass and spasmodic contractions of smooth muscles under alpha-adrenergic receptor-mediated sympathetic stimulation (dynamic component). The mechanical component of BPH can be counteracted with surgery or androgen-modulating drugs, which reduce the size of the prostate (4). On the other hand, alpha-adrenergic receptor antagonists change the tone of the prostatic capsule (and adenoma), thereby decreasing the pressure in the prostatic part of the urethra and bladder neck without affecting the bladder (5). The latter outcome serves as the theoretical basis for using alpha-adrenergic receptor blockers in the treatment of BPH.
Alpha receptors have been divided into ai and cl2 subtypes. Non-selective alpha-adrenergic receptor antagonists were introduced more than two decades ago to alleviate urinary obstruction due to BPH (6,7). Phenoxybenzamine was among the first alpha-adrenergic receptor antagonists used to clinically treat prostatism; however, this and similarly non-selective agents are associated with many adverse effects, particularly cardiovascular responses which manifest as postural hypotension, tachycardia, syncope, and fatigue (8,9). The demonstration that alpha-adrenergic control of prostatic contractions is mediated primarily by ai-, not a2-adrenoceptors, was followed by the introduction of newer ai-selective compounds (10). This second generation of alpha-adrenergic blocking drugs has much less affinity for a2-type receptors. Examples of marketed compounds which exemplify this profile that have been approved by the FDA for the treatment of BPH include terazosin (Hytrin®) and doxazosin (Cardura®) (11-16); the structurally homologous alfuzosin has been introduced primarily in Europe (17-19). While these inherently selective a-i-adrenoceptor antagonists offer the potential benefit of increased urodynamic effects, this property has not been strictly established in a clinical setting. Indeed, high doses of this class of drugs remain associated with systemic side effects, principally vascular events.
During the past decade, progress within the alpha-adrenergic receptor arena has gained considerable momentum. Among key developments was the confirmation of the existence of heterogeneity among ai-receptors with current nomenclature recognizing three subtypes (<xia, aib, and aid) (20). These subtypes have been identified by molecular cloning (aia, a-ib, and aid) and have clearly defined native tissue correlates (21). Recently, an additional ai-receptor subtype (an) was identified that has affinity for prazosin and may be present only in the prostate (22). The significance of this receptor is not well understood and it may not be different from the aia receptor protein, but rather is detected under certain assay conditions (23). A further important result was the recognition that among the a-i-receptor subtypes, the aiA-receptor is chiefly responsible for the contractile tone of the prostatic urethra (24-
27). In the treatment of BPH, blockade of the ai-adrenoceptors in the urinary outflow tract is needed. Blockade of the ai-adrenoceptors in the vascular wall, by contrast, is neither needed nor desirable. This has led to an intensive effort to develop uroselective aia-subtype adrenergic receptor antagonists with the expectation that such agents would have the potential to offer an improved side-effect profile compared to currently available drugs and thereby achieve an enhanced therapeutic response in BPH patients.
It is our objective in this review to present a synopsis of the advances made toward the development of aiA-subtype selective adrenergic receptor antagonists. In this regard, it must be pointed out that the criteria for 'uroselectivity' have not been strictly defined and the term has been used in several contexts resulting in some confusion. An agent may be 'uroselective' in the sense that it has a preferred affinity for the aia-receptor in the prostate (pharmacological), or that, in an animal model, it can affect the prostate and urethra without affecting blood pressure (physiological). A clinically meaningful definition of uroselectivity, which can only be made in man, considers desired effects on obstruction and lower urinary tract symptoms relative to adverse effects (28). In the following chapter, aiA-subtype selective agents are collated according to structural classes and the merits and limitations of key compounds are discussed. Pertinent reviews on this topic have recently appeared (29-31).
Phenoxvethvl amines - Tamsulosin, 1, is the first aiA-receptor subtype selective antagonist approved by the FDA for the treatment of BPH. Its structure is a distant molecular analog of the endogenous alpha-1 receptor agonist norepinephrine; the absolute stereochemistry adjacent to the biogenic amine is (R). Tamsulosin binds with high affinity for the human aiA- and aiD-receptors (pKi = 9.7 and 9.8, respectively) with 10-fold lower affinity for the aiB- receptor (32). It is claimed to be uroselective but this proposal has been contested (33). In a Phase I clinical trial, (0.4 mg, multiple dose) administered as a sustained release formulation was well-tolerated with no significant adverse effects (34). Data from two open-label studies with 1 for treating BPH showed that 84% and 90% of patients, respectively, rated treatment efficacy as good, or very good tolerability (35). The clinical experience with 1 suggests that it may provide better tolerability compared to the non-specific ar antagonists, terazosin and doxazosin. However, it appears that this profile is not a consequence of its inherent pharmacological selectivity but instead is achieved by optimizing its pharmacokinetic (PK) properties via formulation.
A compound structurally related to tamsulosin is the potent and subtype selective indoline analog KMD-3213, 2. The trifluoroethyl group in 2 has been inserted presumably to mitigate O-de-alkylation, a primary metabolic pathway for ± observed in humans (36). As with tamsulosin, the methyl-bearing carbon atom in 2 has the (R)-configuration. KMD-3213 potently binds to the cloned human aia-receptor with a K, value of 0.036 nM and it has 583- and 56-fold lower potency at the ait>- and aid-receptors, respectively (37). Noradrenaline-induced contractions in isolated human prostatic tissue were potently inhibited by 2 with pKs = 9.45, indicating that it has functional activity in this assay similar to 1 (38). aia-Antagonist 2 proved superior to 1 in a rat model testing the effects of intraurethral pressure (IUP) response to the agonist phenylephrine; moreover, 24 hours after oral dosing, a dose-dependent inhibition of IUP was found, whereas the effect of 1 disappeared after 18 hours (39). KMD-3213 has been found to exert longer lasting effects on lower urinary tract function than in vascular tissue (40). This compound is in Phase II in Japan; however, no information regarding the efficacy of 2 in BPH patients has been disclosed (41).
JTH-601, 3, is a high affinity aiA/u-antagonist (pK¡ = 9.4) wherein the achiral linker between the two phenolic nuclei has been truncated relative to 1 and 2 (42). While 3 exhibits only approximately 10-fold selectivity versus the aiB- and ono-receptors, it is reportedly in early clinical development (43). In vivo experiments of 3 support claims of prostatic tissue selectivity (44); 3 is professed to lower IUP and exhibit less pronounced effects on blood pressure than 1 in a phenylephrine-challenge model in rabbits or following ID administration in anaesthetized dogs (45). It is of some pedagogical interest that the principal human metabolite of 3, JTH-601-G1, 4 is a potent antagonist in human prostate (pA2 = 8.12) and exhibits ai-receptor subtype selectivity analogous to the parent compound (46).
Arvlpiperazines - A significant number of N-arylpiperazine ai-adrenoceptor ligands have been investigated even though there is the potential of compounds containing this structural motif to interact with other seven-transmembrane receptors (47,48). The nicotinamide RS-97078, 5, was initially identified based on its functional prostatic selectivity using rabbit bladder neck strips and rat thoracic aortic rings (49). Despite its affinity for dopamine (D2 pki 7.4) and serotonin (5-HTia pki 7.6) receptors, 5 was advanced to the clinic where it has been studied in healthy male volunteers following oral administration of single doses ranging from 2.5 to 30 mg (49). Results from these trials have not been disclosed. A second-generation antagonist to emerge is Ro 70-0004 (6, RS-100975), a compound which appears to have been derived from earlier work on 5 (50,51). Ro 70-0004 binds to the cloned human aia-receptor with high affinity (pKi = 8.9) and selectivity (cm,, 60-fold and aid, 50-fold). In studies of 6 employing human prostatic tissue (HP) and human renal artery (HRA) under conditions of noradrenaline stimulation, pA2 values for HP and HRA were 8.6 and 6.9, respectively. This corresponds to a pA2 ratio (HP/HRA) of 50 and compares favorably with tamsulosin, 1 (HP/HRA = 0.8). In vivo studies with 6 support a selective action on lower urinary tissue. Ro 70-0004 was found to be approximately 100-fold less potent than prazosin at producing postural hypotension during head-up tilt in conscious rats (52); similar results were seen in tilt studies using conscious dogs. In anaesthetized mongrel dogs, 6 was 76-fold more potent at inhibiting hypogastric nerve stimulation-induced rises in IUP verses phenylephrine-induced rises in diastolic blood pressure. In the same study, neither prazosin nor tamsulosin, despite the claimed <xia-receptor subtype selectivity for 1, distinguished between urethral and diastolic blood pressure responses. The observation that ID administration of 6 in dogs results in rapid onset of action (maximal inhibition of IUP responses within 30 minutes) and sustained duration of action (> 4 hours) is noteworthy. Taken together, pre-clinical data indicate that 6 may have advantages over 1.. The assessment of the clinical utility of 6 in the symptomatic treatment of BPH has proceeded to phase II; data from these trials have not been divulged (50).
A 4/-/-1 -benzopyran-8-carboxamide derivative REC15-2739 (7, SB216469) has potent affinity for the human aiA-receptor (pK¡ 9.54), with modest selectivity over cub (pK¡ 7.95) and a-iD (pK¡ 8.87) receptors (53). Studies in anaesthetized dogs indicate that 7 displays some uroselectivity. Under conditions of phenylephrine stimulation, 7 antagonized the increase in IUP with pA2 = 8.74 compared to blood pressure with pA2 = 7.51, indicative of 17-fold uroselectivity. It has been observed that 7 is rapidly cleared from plasma as reflected in its short duration of action in conscious dogs relative to terazosin and 1 (54). It is uncertain to what the extent these PK parameters can be extrapolated to a clinical setting; nonetheless, after entering phase II trials, 7 was withdrawn, allegedly because compound efficacy was not supported by clinical data (55).
A recent report discloses the discovery of a new ai-adrenoceptor antagonist SL 91.0893, 8 (45,56). This arylpiperazine analog exhibits approximately equal affinity for the cloned human ai-receptor subtypes. Nonetheless, 8 displays dose-dependent effects on IUP in the absence of effects on blood pressure possibly because of its distribution to and accumulation in the prostate. The prostatic concentration of 8 is reported to be 10 times that found in plasma one hour post-dose (PO) and rises to 24 times at 6 hours post-dose.
Beginning with screening and literature compounds, a series of hybrid structures that show aiA-receptor selectivity has been generated. Arylpiperazine 9 binds the human aiA-receptor with K¡ = 8.7 nM and exhibits 5300- and 42-fold selectivity over aie and cud, respectively (57). A dose-dependent reduction in phenylephrine-induced increases in IUP was observed in anaesthetized dogs: 50% and 75% reduction at 30 and 300 ng/kg, respectively. Reductions in phenylephrine-induced increases in mean arterial pressure were less: 25-30% reduction at 30-300 ng/kg (57). More recently, homologs of 9 have been disclosed (58,59). The (S)-hydroxy enantiomers 10 and H (K¡, aia = 0.29 nM, 0.33 nM; aib/aia >5600, >6000; aWaia 186, 158, respectively) are slightly less potent but more selective at the aia-receptor than Both homologs exhibit in vivo selectivity comparable to 9, in spite of their improved in vitro profiles. One of these analogs has been selected as a development candidate but the identity of this compound is proprietary (60).
4-Phenyl dihydropyrimidinone 12 is among the most potent arylpiperazine aiA-antagonists reported (61). It displays excellent selectivity versus the other receptor subtypes («¡, aia, cub, a^: 0.12 nM, 190 nM, 250 nM). Although the genesis of 12 can be traced to the calcium channel blocker niguldipine, 13, the former displays >1000-fold selectivity for the aia-receptor; it exhibits a similar selectivity profile for other G-protein coupled receptors like Hi and the family of serotonin receptors. While 12 shows good tissue selectivity (rat prostate, Kb = 0.28 nM vs. rat aorta, Kb = 550 nM) and functional activity in rodents, its limited PK profile in rat (F = 13%, tic = 2 hr) and dog (F = 4%, ti/2 = 2.4 hr) will likely preclude it from clinical evaluation.
Arvlpiperidines - As a class, arylpiperidine-containing compounds comprise the largest and most diverse collection of aia-adrenergic antagonists. Among the first aia-receptor ligands to be identified was the 1,4-dihydropyridine, (S)-(+)-niguldipine
13, which binds with high affinity to the human <xia-receptor (Ki = 0.2 nM); moreover, it exhibits 340- and 630-fold selectivity in binding to the human aia-receptor relative to the human ait>- and aid-receptors (62,63). The Synaptic group effectively eliminated the calcium channel blocking activity of 13 by repositioning the nitro group on the 4-phenyl ring; further ester to amide conversion gave 14 (64). Although 14 has an excellent in vitro binding profile (Ki: aia, 0.18 nM; am, 180 nM; aid, 630 nM; Ca2+, 670 nM), poor PK properties eliminated this compound from development. Additional examples of potent and aia-receptor subtype selective arylpiperidines with appended 1,4-dihydropyridine and dihydropyrimidine ring systems have been reported (65-67). These closely related structural analogs appear not to overcome the PK liabilities of
14. Nonetheless, 14 and its analogs served as prototypes for a second generation of arylpiperidines exemplified by the 1,4-dihydropyrimidinone (DHP) 15 (Ki: aia, 0.2 nM; aib, 260 nM; aid, 350 nM) (68). Less lipophilic and potentially more stable to oxidative metabolism than 14, compound 15 displays incremental improvements in PK properties (rat, F = 19%, ti,2 2 hr; dog F = 26%, ti/2 2.5 hr). Interestingly, although 15 has a relatively short half-life (2 hr) in rats, in an in situ rat prostate assay which measures the inhibition response to a phenylephrine-challenge, the duration of action of 15 was in excess of 4 hours. Development of compound 15 was not pursued because in vitro and in vivo metabolism experiments revealed significant formation of the methyl ester analog of the |i-opioid agonist, nor-meperidine. The potent and selective aia-antagonists 16 (Kj: aia, 0.7 nM; aib, 610 nM; aid, 1280 nM) and 17 (Ki: aia, 0.4 nM; am, 500 nM; aid, 230 nM) separately address metabolism issues related to 15; however, their further development is not apparent (69,70).
A recently disclosed arylpiperidine aia-antagonist is SNAP 7915, 18 (71). The DHP ring in 15 has been truncated to yield a non-racemic oxazolidinone heterocycle which still bears the 3,4-difluorophenyl ring requisite for activity. The preferred configuration of the functional groups at the C-4 and C-5 positions of the
Me oxazolidinone ring is (4S,5S). SNAP 7915 avidly binds to the recombinant human aia-receptor (0.2 nM) and is >700-fold selective versus aib- and aid-receptors. High binding affinity is also observed for rat and dog recombinant aia-receptors (0.3 and 0.2 nM, respectively) indicating no significant species differences in the binding assays. No remarkable cross-reactivity was exhibited by 18 when screened against a panel of more than 30 G-protein coupled receptors. A dose of 3 pg/kg for 18 versus 16.4 pg/kg for 2 was required to block the effect of phenylephrine-induced increases in IUP in anaesthetized mongrel dogs. In contrast, a dose >300 pg/kg was required for 18 to cause a 15 mm Hg (DBP15) drop in diastolic blood pressure; the DBP15 for 2 was 76 pg/kg. Compound 18 displays significant improvements in bioavailability and plasma half-life in rats (25%, 6 hr) and dogs (74%, >12 hr) compared with the foregoing dihydropyridines and dihydropyrimidinones. Future development plans for 18 have not been disclosed.
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