Written by the pioneers of Viagra, the first blockbuster PDE inhibitor drug.
Beginning with a review of the first wave of phosphodiesterase (PDE) inhibitors, this book focuses on new and emerging PDE targets and their inhibitors. Drug development options for all major human PDE families are discussed and cover diverse therapeutic fields, such as neurological/psychiatric, cardiovascular/metabolic, pain, and allergy/respiratory diseases. Finally, emerging chemotherapeutic applications of PDE inhibitors against malaria and other tropical diseases are discussed.
Spiros Liras is the head of the cardiovascular metabolic and endocrine diseases (CVMED) medicinal chemistry department at Pfizer R&D in Cambridge, MA (USA). Previously, he was Senior Director of medicinal chemistry in Neuroscience at Pfizer, working on treatments for addiction, depression, schizophrenia, cognition and Alzheimer's disease. In Neuroscience he worked on multiple PDE targets for the treatment of neuropsychiatric diseases including PDE10, PDE9, PDE2 and PDE1. Dr. Liras obtained his PhD in organic chemistry in 1989 from Iowa State University. He joined Pfizer in 1994 after postdoctoral studies at the University of Texas at Austin. He is a coauthor in more than 70 publications and patents.
Andrew Bell was with Pfizer for over 30 years, following studies at York University (UK). He spent his early career working on PDE inhibitors leading to the inotrope/ vasodilator (PDE3) candidate, nanterinone, and the PDE5 inhibitor, sildenafil (Viagra, Revatio). Soon after the launch of sildenafil in 1998, he was given responsibility for File Enrichment, as part of Pfizer's collaborations with ArQule and Tripos. He has subsequently applied the results of the File Enrichment investment to generate new lead series for multiple projects, including novel series of selective PDE- 4,5,8 and 9 inhibitors. He is currently involved in research into parasitic diseases at Imperial College, London.
Andrew S. Bell and Spiros Liras
The cyclic nucleotide phosphodiesterases (PDEs) are a group of regulatory enzymes that affect intracellular signaling by inactivating the second messengers cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) to the corresponding nucleotides (Figure 1.1). The PDEs are critical in maintaining levels of these cyclic nucleotides within the narrow tolerances required for normal cell operation.
Figure 1.1 Hydrolysis of cyclic nucleotides by PDEs.
The superfamily of PDEs is encoded by 21 different genes that are grouped into 11 subfamilies according to primary sequence homology, composition of the N-terminal regulatory domain, and inhibitor sensitivity. The family has also been split into three sets based on their substrate preferences (Table 1.1). In addition, more than 60 splice variants have been reported.
Table 1.1 Substrate preferences of each class of PDE
cAMP-specific cGMP-specific Mixed
Signal transduction cascades regulated by the PDEs are diverse and include a multitude of central and peripheral processes, such as cell proliferation and cell death, neuroplasticity, gene activation, insulin reaction, locomotion, neurotransmission, metabolism, vascular smooth muscle contraction and growth, and olfactory, taste, and visual responses. Pharmacological intervention of these signaling cascades through selective PDE inhibition is of great therapeutic interest for both central and peripheral targets.
The biological importance and druggability of these enzymes have led to market success with inhibitors for three of the PDE family members across multiple diseases (Table 1.2). The earliest examples include the PDE3 inhibitors amrinone and milrinone for cardiovascular indications, followed by PDE4 inhibitor roflumilast for severe chronic obstructive pulmonary disease. Unfortunately, both PDE3 and PDE4 inhibition result in highly undesirable side effects: sudden cardiac arrest and severe nausea, respectively. As a result, research into novel PDE inhibitors diminished in the late 1980s.
Table 1.2 Peak sales of PDE inhibitors, post-1997
USAN Structure Launch date Target Indication Peak sales ($, million) Amrinone 1983 PDE3 Cardiotonic 20 Milrinone 1989 PDE3 Cardiotonic 228 Roflumilast 2010 PDE4 COPD 104 Sildenafil 1998 PDE5 MED/PH 3119 Vardenafil 2003 PDE5 MED 517 Tadalafil 2003 PDE5 MED/PH/BPH 2222 Udenafil 2009 PDE5 MED 24 Mirodenafil 2009? PDE5 MED 7.5 Avanafil 2012 PDE5 MED 2.4 Abbreviations
: COPD: chronic obstructive pulmonary disease; MED: male erectile dysfunction; PH: pulmonary hypertension; BPH: benign prostatic hypertrophy.
The commercial breakthrough for PDE inhibitors came from the discovery that the PDE5 inhibitor sildenafil was efficacious in the treatment of male erectile dysfunction. The approval of sildenafil under the brand name Viagra® was followed by the commercialization of closely related analogs, vardenafil (Levitra®/Staxyn®/Vivanza®) and tadalafil (Cialis®/Adcirca®). Two other sildenafil analogs (udenafil (Zydena®) and mirodenafil (Mvix®)) have been launched in some countries. A second generation of PDE5 inhibitors is still in development, with the most advanced example, avanafil (Stendra™), launched first in 2012. Sildenafil was also the first PDE5 inhibitor to be approved for the treatment of pulmonary hypertension (Revatio®), an indication closer to its original target, angina. Tadalafil is also approved for the treatment of pulmonary hypertension; in addition, it has been approved for benign prostatic hypertrophy.
The discovery of clinical utility for PDE5 inhibitors triggered a renaissance in PDE research, leading to the identification of the last six subfamilies of PDEs. These included additional cGMP-hydrolyzing enzymes PDEs 6, 9, 10, and 11, which emerged as potential selectivity targets for the PDE5 inhibitors under development. PDE6 is located predominantly in the eye and remains undesirable off-target pharmacology, but the remainder are potential targets for alternative clinical indications. Pharmaceutical research in pursuit of selective PDE inhibitors for various conditions exploded in the 1990s and the field remains highly active today. In all, more than 1000 original patents for various PDEs have appeared in the literature since 1994. Patent activity peaked in 2004–2005 following the characterization and preclinical validation of targets including PDE10 (Chapter 4) and PDE9 (Chapter 7) and breakthroughs in structural biology and molecular modeling that enabled the generation of hypotheses that led to the discovery of selective PDE4 subtype inhibitors (Chapter 3). Since 2004 there has been a steady flow of more than 70 patents a year from major pharmaceutical companies, biotechnology firms, and academia (Figure 1.2). PDE4 and its subtypes, PDE10 and PDE5 (Chapter 2), have dominated patent activity for a broad spectrum of potential therapeutic indications, including schizophrenia, cognitive decline, vascular disease, and stroke, among others.
Figure 1.2 PDE inhibitor patent landscape 1994–2013 (Data source: Thomson_Reuters Integrity).
Although not yet resulting in clinical candidates that have advanced to proof-of-concept studies, several other PDEs have been explored by medicinal chemists in various companies. Recent advances in the field are summarized in separate chapters on PDE1 (Chapter 9), PDE2 (Chapter 5), PDE7 (Chapter 10), and PDE8 (Chapter 8). The only unexploited mammalian PDEs are PDE6 (due to known undesirable visual effects) and PDE11.
Although all of the approved agents target mammalian PDEs, there is evidence for the existence of PDE orthologs across the whole spectrum of eukaryotes including fungi and parasites. The PDEs from Trypanosoma cruzi and Plasmodium falciparum, the causative agents of Chagas disease and malaria, respectively, have received the most interest (Chapter 11).
All of the PDE inhibitors characterized to date have been shown to interact with the catalytic domain of their respective PDE. Despite there being only two substrates, PDEs appear to be capable of tolerating a wide range of chemotypes as inhibitors, which in turn favors the identification of selective inhibitors, often through structure-aided drug design (Chapters 2 and 6). The first crystal structure reported of any PDE domain was that of the catalytic domain of PDE4B in 2000; this was the starting point for a host of structural studies in this important gene family. Crystal structures have been reported of the catalytic domains of PDE1, 2, 3, 4, 5, 7, 8, 9, and 10, by themselves or in complex with inhibitors, substrates, or products. Unfortunately, structural information on PDE regulatory domains is still lacking, and so far only PDE2 has a crystal structure with all its regulatory domains identified.
As a result of the large investment in the biology of PDEs, which occurred after the discovery and commercialization of sildenafil, today the clinical pipeline across the industry remains highly active. Currently, the clinical exploration of the therapeutic potential of numerous PDEs spans many disease areas, including psychiatry, neurology, inflammation, vascular disease, and respiratory diseases, among others. Some of the compounds that highlight the diversity of the current clinical pipeline include PDE4 inhibitors for inflammatory disorders (OCID-2987, Phase 2; GRC-4039, Phase 2). PDE4 inhibitors are also being evaluated for the treatment of cognitive disorders (HT-0712, Phase 2), as topical agents for atopic dermatitis (HT-0712, HT-0712, and AN-2898, all in Phase 2), and for the treatment of depression and anxiety (GSK-356278, Phase 1). The clinical pipeline is also populated with PDE10 inhibitors in various phases of clinical development for the treatment of schizophrenia and Huntington's disease (PF-2545920, Phase 2 for schizophrenia, Phase 1 for Huntington's disease; OMS-182410 and EVP-6308, both in Phase 1 for schizophrenia). PDE5 inhibitors are active in the clinical pipeline for many indications; worth highlighting is Pfizer's...