(19) & (11) EP 2 377 530 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 19.10.2011 Bulletin 2011/42 A61K 31/40 (2006.01) A61K 45/06 (2006.01) A61K 31/4015 (2006.01) A61K 31/403 (2006.01) (2006.01) (2006.01) (21) Application number: 10013573.0 A61K 31/416 A61K 31/4166 A61K 31/4184 (2006.01) A61K 31/505 (2006.01) (2006.01) (2006.01) (22) Date of filing: 20.10.2006 A61P 25/00 A61K 31/401 (84) Designated Contracting States: • Lorrain, Kym, I. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR San Diego HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI California 92124 (US) SK TR • Pires, Jammieson, C. Chula Vista (30) Priority: 21.10.2005 US 729366 P CA 91911 (US) 21.03.2006 US 784605 P • Treuner, Kai 17.07.2006 US 807594 P San Diego California 92122 (US) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: (74) Representative: Roques, Sarah Elizabeth 06826395.3 / 1 940 389 J.A. Kemp & Co. 14 South Square (71) Applicant: Braincells, Inc. Gray’s Inn San Diego, CA 92121 (US) London WC1R 5JJ (GB) (72) Inventors: Remarks: • Barlow, Carrolee This application was filed on 12-10-2010 as a Del Mar divisional application to the application mentioned California 92014 (US) under INID code 62. • Carter, Todd, A. San Diego California 92129 (US) (54) Modulation of neurogenesis by PDE inhibition (57) The instant disclosure describes methods for methods based on use of a PDE agent, optionally in com- treating diseases and conditions of the central and pe- bination with one or more other neurogenic agents, to ripheral nervous system by stimulating or increasing neu- stimulate or activate the formation of new nerve cells. rogenesis. The disclosure includes compositions and EP 2 377 530 A2 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 377 530 A2 2 Description ical and pharmacological properties of the encoded PDEs (e.g., specificity for cAMP and/or cGMP, response RELATED APPLICATIONS to modulatory compounds). [0005] PDE families that specifically/preferentially hy- [0001] This application claims benefit of priority from 5 drolyze cAMP include PDE4, PDE7, and PDE8, whereas U.S. Provisional Patent Applications 60/729,366, filed families that specifically/preferentially hydrolyze cGMP October 21, 2005, 60/784,605, filed March 21, 2006, and include PDE5, PDE6, and PDE9. The PDE1, PDE2, 60/807,594, filed July 17, 2006. All three of these appli- PDE3, PDE10, and PDE11 families show substantial ac- cations are hereby incorporated by reference as if fully tivity agonist both cAMP and cGMP. Many PDE gene set forth. 10 families comprise multiple genes, which give rise to dis- tinct isozymes. For example, the PDE3, PDE6, PDE7, FIELD OF THE DISCLOSURE and PDE8 families each comprise at least two genes (3A, 3B; 6A, 6B; 7A, 7B; 8A, 8B), while the PDE1 family com- [0002] The instant disclosure relates to methods for prises at least three genes (1A, 1B, 1C), and the PDE4 treating diseases and conditions of the central and pe- 15 family comprises at least four genes (4A, 4B, 4C, 4D). In ripheral nervous system by stimulating or increasing neu- addition, the majority of PDE gene transcripts are subject rogenesis via inhibition of cyclic nucleotide phosphodi- to alternative splicing, giving rise to multiple isozymes esterase ("PDE") activity, optionally in combination with within each family. PDE isozymes are differentially ex- another neurogenic agent. The disclosure includes meth- pressed in various tissues, cell types, and subcellular ods based on the application of an PDE inhibitor and20 locations, and numerous PDE isozymes have been de- another neurogenic agent to stimulate or activate the for- tected throughout the CNS. mation of new nerve cells. [0006] Citation of the above documents is not intended as an admission that any of the foregoing is pertinent BACKGROUND OF THE DISCLOSURE prior art. All statements as to the date or representation 25 as to the contents of these documents is based on the [0003] Neurogenesis is a vital process in the brains of information available to the applicant and does not con- animals and humans, whereby new nerve cells are con- stitute any admission as to the correctness of the dates tinuously generated throughout the life span of the or- or contents of these documents. ganism. The newly born cells are able to differentiate into functional cells of the central nervous system and inte- 30 BRIEF SUMMARY OF THE DISCLOSURE grate into existing neural circuits in the brain. Neurogen- esis is known to persist throughout adulthood in two re- [0007] Disclosed herein are compositions and meth- gions of the mammalian brain: the subventricular zone ods for the prophylaxis and treatment of diseases, con- (SVZ) of the lateral ventricles and the dentate gyrus of ditions and injuries of the central and peripheral nervous the hippocampus. In these regions, multipotent neural 35 systems by stimulating or increasing neurogenesis. As- progenitor cells (NPCs) continue to divide and give rise pects of the methods, and activities of the compositions, to new functional neurons and glial cells (for review Gage include increasing or potentiating neurogenesis in cases 2000). It has been shown that a variety of factors can of a disease, disorder, or condition of the nervous system. stimulate adult hippocampal neurogenesis, e.g., adrena- Embodiments of the disclosure include methods of treat- lectomy, voluntary exercise, enriched environment, hip- 40 ing a neurodegenerative disorder, neurological trauma pocampus dependent learning and anti-depressants including brain or central nervous system trauma and/or (Yehuda 1989, van Praag 1999, Brown J 2003, Gould recovery therefrom, depression, anxiety, psychosis, 1999, Malberg 2000, Santarelli 2003). Other factors, learning and memory disorders, and ischemia of the cen- such as adrenal hormones, stress, age and drugs of tral and/or peripheral nervous systems. In other embod- abuse negatively influence neurogenesis (Cameron45 iments, the disclosed methods are used to improve cog- 1994, McEwen 1999, Kuhn 1996, Eisch 2004). nitive outcomes and mood disorders. [0004] Cyclic adenosine monophosphate (cAMP) and [0008] In one aspect, methods of modulating, such as cyclic guanosine monophosphate (cGMP) are ubiquitous by stimulating or increasing, neurogenesis are disclosed. second messengers that mediate a wide range of proc- The neurogenesis may be at the level of a cell or tissue. esses in mammalian cells, including vision, olfaction,50 The cell or tissue may be present in an animal subject or platelet aggregation, aldosterone synthesis, insulin se- a human being, or alternatively be in an in vitro or ex vivo cretion, T cell activation, and smooth muscle relaxation. setting. In some embodiments, neurogenesis is stimulat- Cyclic nucleotide phosphodiesterases ("PDEs") regulate ed or increased in a neural cell or tissue, such as that of intracellular levels of cAMP and cGMP by catalyzing their the central or peripheral nervous system of an animal or hydrolysis to the corresponding nucleotide 5’-monophos- 55 human being. In cases of an animal or human, the meth- phates. Over 20 PDE genes have been cloned, encoding ods may be practiced in connection with one or more 11 gene families (PDE1- PDE11), which are classified ac- diseases, disorders, or conditions of the nervous system cording to sequence homology, as well as the biochem- as present in the animal or human subject. Thus, em- 2 3 EP 2 377 530 A2 4 bodiments disclosed herein include methods of treating the method may be used to improve, maintain, or stabilize a disease, disorder, or condition by administering at least mood in a subject or patient Of course the method may one neurogenesis modulating agent having inhibitory ac- be optionally combined with any other therapy or condi- tivity against a cyclic nucleotide phosphodiesterase tion used in the treatment of a mood disorder. ("PDE"), hereinafter referred to as a "PDE agent". A PDE 5 [0014] In a third aspect, the disclosed methods include agent may be formulated or used alone, or in combination identifying a patient suffering from one or more diseases, with one or more additional neurogenic agents, such as disorders, or conditions, or a symptom thereof, and ad- another PDE agent or a non-PDE agent. ministering to the patient a PDE agent, optionally in com- [0009] The disclosure thus includes a method of using bination with one or more other neurogenic agents, as a chemical entity as a PDE agent to increase neurogen- 10 described herein. In some embodiments, a method in- esis. In some embodiments, a chemical entity used as cluding identification of a subject as in need of an in- an agent is a therapeutically or pharmaceutically accept- crease in neurogenesis, and administering to the subject able reversible PDE inhibitor. Alternatively, an accepta- a PDE agent, optionally in combination with one or more ble irreversible PDE inhibitor may also be used in some other neurogenic agents is disclosed herein. In other em- embodiments of the disclosure. Additional embodiments 15 bodiments, the subject is a patient, such as a human comprise an inhibitor that is a tertiary amine which cross- patient es the blood brain barrier. [0015] Another aspect of the disclosure describes a [0010] While a PDE agent may be considered a "direct" method including administering a PDE agent, optionally agent in that it has direct activity against a PDE by inter- incombination with one or more other neurogenicagents, actions therewith, the disclosure includes a PDE agent 20 to a subject exhibiting the effects of insufficient amounts that may be considered an "indirect" agent in that it does of, or inadequate levels of, neurogenesis. In some em- not directly interact with a PDE.