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This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published.

Regional haemodynamic responses to a continuous, 4-day infusion of the selective phosphodiesterase type 5 inhibitor, UK-357,903 (0.133 or 1.33 mg kg−1 h−1) were measured in conscious spontaneously hypertensive rats, and compared with those of enalapril (1 mg kg−1 h−1). Both doses of UK-357,903 caused modest reductions in mean blood pressure that were not dose-dependent and only significantly different from the vehicle effects on Day 1 of the study (mean −11.8 and −15.3 mmHg for low and high doses, respectively). UK-357,903 had mesenteric and hindquarters vasodilator effects, which were, again, similar for both dose levels and only significantly different from vehicle on Day 1. Neither dose of UK-357,903 affected renal vascular conductance or heart rate. Although the haemodynamic effects of UK-357,903 were not clearly dose-related and some appeared to wane with time, geometric mean plasma levels of UK-357,903 increased in proportion to dose, and were sustained throughout the infusion period. Furthermore, plasma cyclic guanosine monophosphate, a biomarker of phosphodiesterase 5 inhibition, was persistently elevated, and increased with increasing dose. Enalapril caused a fall in mean blood pressure on day 1 (−14.1 mmHg) that was associated with dilatation in renal, mesenteric and hindquarters vascular beds. The haemodynamic effects of enalapril were sustained or increased over the 4-day infusion, although plasma free drug levels were stable. In conclusion, we have shown regional and temporal changes in the haemodynamic effects of UK-357,903, which may be due to activation of compensatory mechanisms, but there were no signs of functional compensation to the cardiovascular effects of enalapril. British Journal of Pharmacology (2004) 141, 114–122. doi:10.1038/sj.bjp.0705581

Purpose: The effects of sildenafil, a highly selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase type 5, on erectile function in the anesthetized dog were evaluated.Materials and Methods: In pentobarbital-anesthetized dogs, increases in intracavernosal pressure in the corpus cavernosum and penile blood flow were induced by pelvic nerve stimulation over a frequency range of 1 to 16 hertz. The effects of increasing doses of sildenafil on electrically stimulated intracavernosal pressure, penile blood flow, blood pressure, and heart-rate were evaluated. In parallel experiments, the effects of the nitric oxide synthase inhibitor N omega-Nitro-L-Arginine (L-NOArg) on these same parameters also were assessed.Results: The effects of nerve stimulation on intracavernosal pressure and blood flow to the penis were blocked by L-NOArg, 0.1-3 mg./kg., in a dose-related manner, confirming the important role of nitric oxide in producing erections. Sildenafil, 1-100 micro g./kg administ...

The design, synthesis and biological properties of homochiral non-steroidal inhibitors of both isozymes of human 5α-reductase are described. The o-hydroxy aniline moiety of the initial lead (1) can be replaced by a 3-acyl indole isostere, whilst the minimum energy conformation of the benzyl ether in the potent inhibitor (3) is mimicked by the conformationally locked benzodioxolane system in the potent non-steroidal inhibitor (7). Pharmacokinetics and oral efficacy in a rat model of BPH are presented for (3) and (7).

In this Letter we present data for a novel series of ICS for the treatment of asthma. 'Inhalation by design' principles have been applied to a series of highly potent steroidal GR agonists, with a focus on optimising the potential therapeutic index in human. Pharmacokinetic properties were tuned with high intrinsic clearance and low oral bioavailability in mind, to minimise systemic exposure and reduce systemically driven adverse events. High CYP mediated clearance as well as glucuronidation were targeted to achieve high intrinsic clearance coupled with multiple routes of clearance to minimise drug-drug interactions. Furthermore, pharmaceutical properties such as stability, crystallinity and solubility were considered to ensure compatibility with a dry powder inhaler. This work culminated in the identification of the clinical candidate 15, which demonstrates preclinically the desired efficacy and safety profiles confirming its potential as an inhaled agent for the treatment of asthma.

The design, synthesis and biological properties of homochiral non-steroidal inhibitors of both isozymes of human 5α-reductase are described. The o-hydroxy aniline moiety of the initial lead (1) can be replaced by a 3-acyl indole isostere, whilst the minimum energy conformation of the benzyl ether in the potent inhibitor (3) is mimicked by the conformationally locked benzodioxolane system in the potent non-steroidal inhibitor (7). Pharmacokinetics and oral efficacy in a rat model of BPH are presented for (3) and (7).

The regional hemodynamic responses to continuous 4-day infusion of UK-357,903 [1-ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-2-(2-methoxyethoxy)-5-pyridylsulphonyl}piperazine] (266 microg kg(-1) h(-1)) alone and in combination with a low dose of enalapril (10 microg kg(-1) h(-1)) were measured in conscious spontaneously hypertensive rats to test the hypothesis that the renin-angiotensin system may influence the cardiovascular consequences of inhibition of phosphodiesterase 5 (PDE5) by UK-357,903 or vice versa. UK-357,903 alone caused a fall in mean blood pressure (-12.1 mm Hg) associated with vasodilatation in the mesenteric and hindquarters vascular beds. The only way in which the effects of enalapril given alone differed significantly from those of the vehicle was in causing mesenteric vasodilatation, which developed over the 4 days of infusion. UK-357,903 given in combination with enalapril caused hypotension (-17.8 mm Hg) and vasodilatation in the renal, mesenteric, and hindquarter vascular beds. There was evidence of a significant interaction between the effects of the two compounds on renal Doppler shift and vascular conductance with the combined action of the two compounds being greater than the sum of their individual effects. However, although there was a trend for the combination to have greater effects than either of the individual agents on blood pressure and mesenteric vascular conductance, there was no statistical evidence of an interaction. The results indicate that inhibition of the renin-angiotensin system uncovers additional renal vasodilator effects of UK-357,903, and/or inhibition of PDE5 enhances the renal vasodilator effects of angiotensin-converting enzyme inhibition.

Stromal cells derived from benign prostatic hyperplasia synthesize and secrete measurable levels of insulin-like growth factor (IGF). Seventy-two-hour conditioned medium obtained from these cells contains IGF-II at levels ranging from 125-177 ng/mL.10(6) cells. IGF-I is almost undetectable. RT-PCR analysis has demonstrated that the genes for both the type I IGF receptor (IGF-IR) and the type II IGF receptor (IGF-IIR) are expressed by benign stromal cells in vitro. Competition binding analysis for IGF-I and IGF-II confirmed the existence of binding sites for both ligands with respective Kd and binding capacities of 4.9 x 10(-9) mol/L and 6.6 x 10(5) sites/cell and 4.7 x 10(-9) mol/L and 3.8 x 10(6) sites/cell. Under serum-free conditions, IGF-I and IGF-II at 500 ng/mL induce 80% and 113% increases in stromal cell density, respectively, over a 96-h period. Incubation with the IGF-IR-neutralizing antibody alpha IR3 (50 micrograms/mL) reduces the rate of stromal cell proliferation by approximately 60-80% even in the presence of stimulatory concentrations of IGFs. Camptothecin-induced apoptosis is inhibited by the addition of IGF-I and -II (500 ng/mL). alpha IR3 suppresses these survival signals and itself induces cell death in the prostatic stroma. The data suggest that IGF-IR is a pivotal molecule in prostatic stromal cell maintenance, and that specific antagonism may offer a novel means of controlling the fibromuscular expansion characteristic of benign prostatic hyperplasia.