Alpha(v)beta(3) integrin antagonism as a treatment of osteoporosis

An estimated 10 million Americans over the age of 50 years old suffer from osteoporosis and a further 32.9 million have low bone mass, placing them at an increased risk for developing this condition. Patients with these conditions carry an increased risk of sustaining fractures, which are both clinically problematic and costly to healthcare systems, and the development of new osteoporosis treatments therefore offers immense opportunities to the pharmaceutical industry. The global osteoporosis therapies market, including estrogen replacement therapy drugs was estimated at $5.5 billion in 2001 and projected to double by 2008 in the face of population aging, decreased bone quality and increased awareness of osteoporosis.

In a recent DiscoveryDossier we analyze therapeutic and pharmaceutical opportunities in the field of osteoporosis (click here for access). Once dominated by hormone replacement therapies (HRTs), the field of osteoporosis has undergone three major changes since the mid-1990's. First, the bisphosphonate Fosamax was launched in 1995. Since this launch the bisphosphonates have become the most effective means of limiting bone loss. Then, in January 1998 Eli Lilly launched Evista (raloxifene), the first selective estrogen receptor modulator and as a result the concept of combining the beneficial effects of estrogen antagonism (ie anti-cancer activity) and agonism (ie bone health) became a real therapeutic possibility. Most recently the FDA has approved the use of the parathyroid hormone Forteo (teriparatide), the first treatment for osteoporosis with anabolic activity.

Bone remodeling represents a balance between the activities of osteoclasts that remove bone and osteoblasts that synthesize bone matrices and mineralize them. The search for new molecular targets that are involved in the regulation of these cells continues in order to identify improved therapies. In recent years, it has been shown that alpha(v)beta(3) integrin is involved in the bone remodeling process. Highly expressed in osteoclasts, this receptor is implicated in the adhesion, activation, and migration of osteoclasts on the bone surface as well as osteoclast polarization. A number of arg-gly-asp (RGD)-containing proteins, including osteopontin, bone sialoprotein, vitronectin, and fibrinogen, are known to bind to alpha(v)beta(3) integrin and regulate bone remodeling. On the other hand, antibodies to alpha(v)beta(3) integrin, RGD-peptides, and small-molecule alpha(v)beta(3) integrin antagonists have been shown to be efficacious in models of bone resorption, providing strong evidence that inhibitors of this integrin would be useful agents for the treatment of osteoporosis.

Researchers from Merck have been actively involved in the rational design of small-molecule alpha(v)beta(3) integrin antagonists using the RGD-triad as a start point. Consequently Cripes et al have recently described a series of imidazolidinones that have excellent in vitro potency and display good pharmacokinetics in rats and dogs. A lead from this series has been shown to be efficacious in rat models of bone resorption however extensive binding to human plasma proteins (>98%) precluded further development. Most recently therefore, Hutchinson et al conducted further SAR studies leading to the identification of a potent and highly selective alpha(v)beta(3) integrin antagonist with reduced binding to plasma proteins and improved pharmacokinetics that has been selected for evaluation in the treatment of osteoporosis in human clinical trials. This candidate was evaluated in ovariectomized animals, a model of post-menopausal osteoporosis. Daily oral dosing at 10 and 30mg/kg reversed relative bone loss in the distal femoral metaphysis of rats, and the efficacy of this alpha(v)beta(3) integrin antagonist was similar to therapeutic doses of the reference compound, Fosamax. Efficacy was also reported in ovariectomized rhesus monkey using urinary markers as an indication of bone degradation.

Oral bisphosphonates are well established for the treatment and prevention of postmenopausal osteoporosis; however, they are poorly absorbed from the gastrointestinal tract and have been associated with GI adverse events. Thus, current dosing guidelines recommend that the patient not eat or lie down for at least 30 minutes after taking oral bisphosphonates. Although adverse effects are minimal when these dosing guidelines are followed, the use of oral bisphosphonates can be inconvenient and may be associated with reduced compliance. The development of effective small-molecule alpha(v)beta(3) integrin antagonists such as the candidate described here may therefore offer an alternative and possibly more acceptable approach to osteoporosis.

Entry date Monday, December 08, 2003

Adapted from Hutchinson et al, J Med Chem. 2003 Oct 23;46(22):4790-4798.