PF-489791

Diabetic nephropathy (DN) is the leading cause of ESRD worldwide. Reduced bioavailability or uncoupling of nitric oxide in the kidney, leading to decreased intracellular levels of the nitric oxide pathway effector molecule cyclic guanosine monophosphate (cGMP), has been implicated in the progression of DN. Preclinical studies suggest that elevating the cGMP intracellular pool through inhibition of the cGMP-hydrolyzing enzyme phosphodiesterase type 5 (PDE5) might exert renoprotective effects in DN. To test this hypothesis, the novel, highly specific, and long-acting PDE5 inhibitor, PF-00489791, was assessed in a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel group trial of subjects with type 2 diabetes mellitus and overt nephropathy receiving angiotensin converting enzyme inhibitor or angiotensin receptor blocker background therapy. In total, 256 subjects with an eGFR between 25 and 60 ml/min per 1.73 m2 and macroalbuminuria defined by a urinary albumin-to-creatinine ratio >300 mg/g, were randomly assigned 3:1, respectively, to receive PF-00489791 (20 mg) or placebo orally, once daily for 12 weeks. Using the predefined primary assessment of efficacy (Bayesian analysis with informative prior), we observed a significant reduction in urinary albumin-to-creatinine ratio of 15.7% (ratio 0.843; 95% credible interval 0.73 to 0.98) in response to the 12-week treatment with PF-00489791 compared with placebo. PF-00489791 was safe and generally well tolerated in this patient population. Most common adverse events were mild in severity and included headache and upper gastrointestinal events. In conclusion, the safety and efficacy profile of PDE5 inhibitor PF-00489791 supports further investigation as a novel therapy to improve renal outcomes in DN.

Clinical studies with our male erectile dysfunction medicine, sildenafil, identified several additional indications for PDE5 inhibitors. Since these include disease indications requiring chronic treatment and/or single dose daily dosing in order to be competitive, we sought novel agents with an excellent safety profile, and in particular, no potential for off-target activity against other PDE family members.We were able to identify a second generation PDE5 agent meeting these requirement based on a HTS–derived series. Key elements in discovery were the focus on physicochemistry and pharmacokinetics throughout the programme, together with the use of co-crystal structure data to guide design and identification of a parallel chemistry amenable, wide synthetic scope template. These elements enabled rapid discovery of a proprietary lead 3 with inherently good physicochemistry, a novel aminopyridine pharmacophore and PDE6 selectivity. Further optimisation provided advanced acidic, neutral and basic leads. Finally, a potent and selective acidic clinical candidate 13 with low clearance and an outstanding safety profile was identified. The excellent pre-clinical profile derived from our property-based strategy has successfully translated to once daily oral pharmacokinetics in man.