title: Advances in small molecules promoting neurotrophic function.
abstract: Nerve growth factor (NGF) and other members of the neurotrophin family are critical for the survival and differentiation of neurons and have been implicated in the pathophysiology of numerous disease states. Although the therapeutic potential of neurotrophins has generated much excitement over the past decade, inconvenient pharmacokinetics and adverse side-effect profiles have limited the clinical usefulness of neurotrophic factors themselves. Compounds that mimic neurotrophin signaling and overcome the pharmacokinetic and side-effect barriers may have greater therapeutic potential. Here, we review the progress to date of clinical trials with direct neurotrophin modulators and describe alternative strategies to target (modulate) neurotrophin production and/or their signal transduction pathways. Particular emphasis is placed on small molecules that are able to modulate neurotrophin function in diseases of the nervous system. These alternative strategies show promise in preclinical studies, with some advancing into clinical development. Moreover, the recognition that clinically effective therapeutics, such as antidepressants and immunophilin ligands, can modulate neurotrophin function suggests that the concept of small molecule therapeutics that promote neurotrophic function may still be viable.
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba 305-8585, Japan. raymond.price@acucela.com
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Price
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Milne
authors.forename: John
authors.initials: J
authors.lastname: Sharkey
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000502:physiology / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D020932:Nerve Growth Factor / Q000096:biosynthesis / Q000502:physiology / Q000627:therapeutic use; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000502:physiology* / Q000627:therapeutic use; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor