Selective Phospholipase A2 Inhibitors of Neurological Diseases

Background

The past two decades has resulted in a marked increase in our knowledge about phospholipase A₂ (PLA₂) enzymes. The PLA₂ superfamily of enzymes has been divided into four main types: secreted sPLA₂s, cytosolic cPLA₂s, calcium-independent iPLA₂s, and lipoprotein-associated/PAF acetyl hydrolase LpPLA₂s.

The association of the different types of PLA₂s with diverse indications has justified pharma’s interest in developing selective inhibitors to the specific types. Undeveloped indications exist in the central nervous system (CNS) and the ability to target these underserved indications would enable a new means for targeting the underlying inflammatory causes of numerous diseases.

Technology Description

Researchers at UC San Diego and their international collaborators have developed a portfolio of issued and pending patents disclosing composition of matter and methods for selectively inhibiting s, i, and cPLA₂s. Compositions span three, distinct chemical classes (amides, oxoamides, and fluoroketones) and proprietary methods claim treatment of various neurological illnesses, including hyperalgesia, multiple sclerosis (MS), and spinal cord injury. More detailed, non-confidential information is available in the Detailed Description.

Advantages

Proof of concept and IP is available for compositions of matter, target enzymes, and disease applications for novel relatively unexplored targets for a variety of neurological diseases for which good treatment options do not exist.

State Of Development

In vitro and in vivo experiments validate a suite of potent inhibitors of PLA₂, with differential specificity for the sPLA₂, cPLA₂, and iPLA₂. Specifically, sPLA₂ inhibitors markedly improve functional recovery and enhance tissue protection and axon regeneration in the mouse spinal-cord contusion injury model, while cPLA₂ and iPLA₂ inhibitors reduce the severity of disease in a widely used animal model of MS (experimental autoimmune encephalomyelitis, or EAE) and iPLA₂ inhibitors protect in rat models of hyperalgesia.

Intellectual Property Info

Issued and pending U.S. patents include: 7,745,489, 5,464,754, WO/2009/009449, and WO/2008/122119.

Numerous foreign issued patents are available online and unpublished applications are available under confidentiality. See also WO/2010/011686, Amides as Inhibitors of Human Secreted Phospholipase A2.

Other Information

See related case SD1998-078 as described in U.S. patent number 7,294,496.

Related Materials

• See the inventor’s Web site at http://cobra.ucsd.edu.
• Barbayianni E, Stephens D, Grkovich A, Magrioti V, Hsu YH, Dolatzas P, Kalogiannidis D, Dennis EA, Kokotos G. (2009) 2-Oxoamide inhibitors of phospholipase A₂ activity and cellular arachidonate release based on dipeptides and pseudodipeptides. Bioorg Med Chem 17(13):4833-43.
• Baskakis C., V. Magrioti, N. Cotton, D. Stephens, V. Constantinou-Kokotou, E.A. Dennis, and G. Kokotos. (2008) Synthesis of Polyfluoro Ketones for Selective Inhibition of Human Phospholipase A₂ Enzymes. J Med Chem., 51 (24), 8027-8037.
• Lucas KK, Svensson CI, Hua XY, Yaksh TL, Dennis EA. (2005) Spinal phospholipase A₂ in inflammatory hyperalgesia: role of group IVA cPLA₂. Br J Pharmacol 144(7):940-52.
• Six DA, Barbayianni E, Loukas V, Constantinou-Kokotou V, Hadjipavlou-Litina D, Stephens D, Wong AC, Magrioti V, Moutevelis-Minakakis P, Baker SF, Dennis EA, Kokotos G. (2007) Structure Activity Relationship of 2-Oxoamide Inhibition of Group IVA Cytosolic phospholipase A₂ and Group V Secreted Phospholipase A₂, J Med Chem, 50, 4222-35.
• Stephens D., E. Barbayianni, V. Constantinou-Kokotou, A. Peristeraki, D.A. Six,J. Cooper, R. Harkewicz, R.A. Deems, E.A. Dennis, and G. Kokotos. (2006) Differential Inhibition of Group IVA and Group VIA Phospholipases A₂ by 2-Oxoamides, J Med Chem, 49 (9), 2821-2828.
• Yaksh TL, Kokotos G, Svensson CI, Stephens D, Kokotos CG, Fitzsimmons B, Hadjipavlou-Litina D, Hua XY, Dennis EA. (2006) Systemic and intrathecal effects of a novel series of phospholipase A₂ inhibitors on hyperalgesia and spinal prostaglandin E2 release. J Pharmacol Exp Ther 316(1):466-75.
• V. Magrioti, G. Kokotos. (2010) Phospholipase A₂ inhibitors as potential therapeutic agents for the treatment of inflammatory diseases, Exp Opin Ther Pat, 20 (1), 1-18.

Patent Status