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Alacepril a Neuronal Positive Control

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US 2008O167291A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0167291 A1 Barlow et al. (43) Pub. Date: Jul. 10, 2008 (54) NEUROGENESIS BY MODULATING Publication Classification ANGOTENSIN (51) Int. Cl. (75) Inventors: Carolee Barlow, Del Mar, CA A6II 3/55 (2006.01) (US); Todd A. Carter, San Diego, A6II 3/40 (2006.01) CA (US); Kai Treuner, San Diego, A63L/466 (2006.01) CA (US); Kym I. Lorrain, San A 6LX 3L/95 (2006.01) Diego, CA (US) A6II 3/522 (2006.01) CI2N 5/06 (2006.01) Correspondence Address: A6IP 25/00 (2006.01) TOWNSEND AND TOWNSEND AND CREW, A63L/403 (2006.01) LLP A6II 3/53 (2006.01) TWO EMBARCADERO CENTER, EIGHTH A6II 3/445 (2006.01) FLOOR A6II 3/4I (2006.01) SAN FRANCISCO, CA 94111-3834 (52) U.S. Cl. .................... 514/212.07: 514/423: 514/381: (73) Assignee: BrainCells, Inc., San Diego, CA 514/392: 514/319; 514/567; 514/243: 514/263.34; (US) 514/412; 435/377 (21) Appl. No.: 11/746,539 (57) ABSTRACT (22) Filed: May 9, 2007 The instant disclosure describes methods for treating diseases and conditions of the central and peripheral nervous system Related U.S. Application Data by stimulating or increasing neurogenesis. The invention (60) Provisional application No. 60/746,859, filed on May includes compositions and methods based on modulation 9, 2006, provisional application No. 60/807,594, filed angiotensin activity to stimulate or activate the formation of on Jul. 17, 2006. new nerve cells. Neuronal Differentiation (TUJ1) 100 9 O Alacepril A Neuronal Positive Control 2 O 10-8.5 10-7.5 106.5 10-5.5 10-4.5 Conc(M) Patent Application Publication Jul. 10, 2008 Sheet 1 of 17 US 2008/0167291 A1 ls r O y - O H L s' L O 9 y w t S SN as S Li, 5 N g v s E - 8 5. S- O < 2 & ce oO coS NS Cto toC rC (S enS O.- O. seC Ionuop empisod 0 le3e Patent Application Publication Jul. 10, 2008 Sheet 2 of 17 US 2008/0167291 A1 L rt O y s 2 S - l& S9 as s N a E 5 s 5 L. SE ()g Se& O8 s -5. 9 g 2 - S. S S S Ct c O. O. O. O. O. O. e O. co N to to t c n - w 3. Olu OO eA)SOJO Jule3e Patent Application Publication Jul. 10, 2008 Sheet 3 of 17 US 2008/0167291 A1 L r O y F - D Li L 9 Se su, er E o 5. Q S.N : S NS9 O Se& U .2 s = 3 S is l Z .RC 5. rO U) v . A. () - 2 a seS. oO. OO.S. O.N. S.C. L.C. vC S. SN seS o s 3. O.I.LOO 8A)SOJO ue3e Patent Application Publication Jul. 10, 2008 Sheet 4 of 17 US 2008/0167291 A1 L rt C wn - D H l y L C O w N E 9 s S SB E L. C. S.S E OO & 3 S. 5. s o L r e S. S. O cy " O a e a co N to to ri () en - w s Olu OO eA)SOJO le3.e. Patent Application Publication Jul. 10, 2008 Sheet 5 of 17 US 2008/O167291 A1 L rt y S - D t : 9 Y t s S SE E to S is O & O S. E O 9 () O d. s 2 (5 s s O is - 2 3. vu OILO) eAISOJO Jule3e Patent Application Publication Jul. 10, 2008 Sheet 6 of 17 US 2008/0167291 A1 Figure 6: Human Neurogenesis Assay: Benazepril Patent Application Publication Jul. 10, 2008 Sheet 7 of 17 US 2008/0167291 A1 Figure 7: Human Neurogenesis Assay: Trandolapril Patent Application Publication Jul. 10, 2008 Sheet 8 of 17 US 2008/0167291 A1 Figure 8: Human Neurogenesis Assay: Candesartan Patent Application Publication Jul. 10, 2008 Sheet 9 of 17 US 2008/O167291 A1 Figure 9: Human Neurogenesis Assay: Temisartan Patent Application Publication Jul. 10, 2008 Sheet 10 of 17 US 2008/0167291 A1 Figure 10: Human Neurogenesis Assay: budilast + Captopril Neuronal Differentiation --lbudilast + Captopril O'Captopril A 'budilast 1 . 10 Captopril Concentration 10-8.5 10-8.0 10-7.5 10-70 10-6.5 10-6-0 10-5.5 10-50 10-4.5 10-40 H 10-9.0 10-8.5 10-8.0 10-7.5 10-70 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 Conc (M) Ibudilast Concentration Patent Application Publication Jul. 10, 2008 Sheet 11 of 17 US 2008/0167291 A1 Figure 11: Human Neurogenesis Assay: Enoximone + Captopril Neuronal Differentiation (TUJ1) --Enoximone + Captopril 120 -0. Captopril 110 - Ari EnoximOne 6 O 10 1.-: Captopril and Enoximone O SSSS as ess was as a Concentration 10-8.5 10-8.0 10-7.5 10-7.0 10-6.5 10-6-0 10-5.5 10-5.0 10-4.5 10-4.0 Conc (M) Patent Application Publication Jul. 10, 2008 Sheet 12 of 17 US 2008/0167291 A1 Figure 12: Human Neurogenesis Assay: budilast + Candesartan Neuronal Differentiation (TUJ1) --budilast + Candesartan budilast Candesartan 65 55 45 35 25 15 5 Candesartan Concentration -i. 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-50 10-4.5 10-40 -8.5 -8.0 -7.5 -7.0 -6.5 -6.0 -5.5 -5.0 -45 -4.0 Conc(M) mummum 10-9.0 10-8.5 10-8-0 10-75 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 Conc (M) budilast Concentration Patent Application Publication Jul. 10, 2008 Sheet 13 of 17 US 2008/0167291 A1 Figure 13: Human Neurogenesis Assay: Captopril + Baclofen Captopril Baclofen Neuronal Differentiation (TUJ1) 110 H Captopril/Baclofen COMBO 90 A' Captopril -v- Baclofen 10-8.5 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-4.0 Conc(M) Patent Application Publication Jul. 10, 2008 Sheet 14 of 17 US 2008/0167291 A1 Figure 14: Human Neurogenesis Assay: Captopril + Donepezil Captopril Donepezil Neuronal Differentiation (TUJ1) so Captopril/Donepezil COMBO 150- A Captopril 140- -V. Donepezil 130 A. 120 110 100 90 80 70 60 50 40 30 20 10 -1 s 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-4.0 Conc(M) Patent Application Publication Jul. 10, 2008 Sheet 15 of 17 US 2008/0167291 A1 Figure 15: Human Neurogenesis ASSay: Captopril + Vardenafil Captopril Vardenafil Neuronal Differentiation (TUJ1) 120- H Captopril/Wardenafil COMBO 110- A 'Captopril -v- Vardenafi 6 O 10-8.5 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-4-0 Conc(M) Patent Application Publication Jul. 10, 2008 Sheet 16 of 17 US 2008/0167291 A1 Figure 16: Human Neurogenesis Assay: Telmisartan + Rolipram Telmisartan Rolipram Neuronal Differentiation (TUJ1) -HTelmisartan/Rolipram COMBO -A Telmisartan -v. Rolipram 5 O Telmisartan Concentration 10-9.5 10-9.0 10-8.5 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-8.5 10-8.0 10-75 10-7.0 106.5 10-6-0 10-55 10-50 104.5 10-40 Conc(M) Rolipram Concentration Patent Application Publication Jul. 10, 2008 Sheet 17 of 17 US 2008/0167291 A1 Figure 17: Human Neurogenesis ASSay: Theophylline + Captopril Neuronal Differentiation (TUJ1) 110 100 - O - Captopril 90 ---Theophylline 80 -0-Combination 70 60 50 40 30 20 10 -10 10-8.5 10-7.5 10-6.5 10-5.5 10-4.5 US 2008/0167291 A1 Jul. 10, 2008 NEUROGENESIS BY MODULATING has been observed to be more potent. AII acts as a vasocon ANGOTENSIN strictor to raise arterial blood pressure and decrease blood flow. AII also acts on the adrenal cortex, which leads to the RELATED APPLICATIONS release of aldosterone. In turn, aldosterone acts in the kidney 0001. This application claims benefit of priority to U.S. to cause resorption of sodium and water from urine. The result Provisional Applications 60/746,859, filed May 9, 2006, in an increase in the fluid volume of blood. which is incorporated by reference as if fully set forth. This 0006. The two systems are activated following blood loss application also claims benefit of priority to U.S. Provisional or a drop in blood pressure. Other components of the systems Application 60/807,594, filed Jul. 17, 2006; and U.S. appli are the AII receptor(s) that mediate AII activity. Angiotensin cation Ser. No. 1 1/551,667, filed Oct. 20, 2006, both of which receptors are G protein-coupled receptors which bind AII as a are incorporated by reference as if fully set forth. ligand. Subtypes of the receptors include AT and AT, both of which bind AII, and the AT and AT receptors. FIELD OF THE INVENTION 0007 Both the receptors and ACE have been the targets of manipulation to treat hypertension (high blood pressure) and 0002 The instant invention relates to methods for treating other conditions. AII receptor antagonists, also referred to as diseases and conditions of the central and peripheral nervous angiotensin receptor blockers or ARBs, AT1-receptor antago system by stimulating or increasing neurogenesis via modu nists, or Sartans, are used to antagonize AII activity by pre lation of angiotensin activity.
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  • Angiotensin-Converting Enzyme (ACE)

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    Angiotensin-converting Enzyme (ACE) Angiotensin-converting enzyme (ACE) indirectly increases blood pressure by causing blood vessels to constrict. ACE does that by converting angiotensin I to angiotensin II, which constricts the vessels. ACE, angiotensin I and angiotensin II are part of the renin-angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. ACE is secreted in the lungs and kidneys by cells in the endothelium (inner layer) of blood vessels. It has two primary functions: ACE catalyses the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor in a substrate concentration-dependent manner. ACE degrades bradykinin, a potent vasodilator, and other vasoactive peptides. These two actions make ACE inhibition a goal in the treatment of conditions such as high blood pressure, heart failure, diabetic nephropathy, and type 2 diabetes mellitus. Inhibition of ACE (by ACE inhibitors) results in the decreased formation of angiotensin II and decreased metabolism of bradykinin, leading to systematic dilation of the arteries and veins and a decrease in arterial blood pressure. www.MedChemExpress.com 1 Angiotensin-converting Enzyme (ACE) Inhibitors & Activators (R)-MLN-4760 Alamandine Cat. No.: HY-19414A Cat. No.: HY-P3108 (R)-MLN-4760, the R-enantiomer of MLN-4760, is an Alamandine, a member of the renin-angiotensin ACE2 inhibitor, with an IC50 of 8.4 μM. system (RAS), a vasoactive peptide, is an (R)-MLN-4760 is the less active isomer. endogenous ligand of the G protein-coupled receptor MrgD. Alamandine targets to protect the kidney and heart through anti-hypertensive actions. Purity: >98% Purity: 98.95% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg, 10 mg, 25 mg Size: 5 mg Angiotensin (1-7) Angiotensin (1-7) (acetate) (Ang-(1-7)) Cat.
  • Angiotensin Converting Enzyme Inhibitors in the Treatment of Hypertension

    Angiotensin Converting Enzyme Inhibitors in the Treatment of Hypertension

    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Publications of the IAS Fellows CHEMISTRY – STRUCTURE, SYNTHESIS AND DYNAMICS Angiotensin converting enzyme inhibitors in the treatment of hypertension Bhaskar J. Bhuyan and Govindasamy Mugesh* Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560 012, India verting enzyme’ (ACE). Further, ACE is also responsible Angiotensin converting enzyme (ACE) catalyses the conversion of angiotensin I (Ang I) to angiotensin II for the elevation of BP by cleaving the terminal dipeptide (Phe–Arg) of vasodilator hormone bradykinin to its (Ang II). The ACE activity directly related to hyperten- 5,6 sion as Ang II is the blood pressure regulating hormone. inactive form (bradykinin 1–7, Figure 1) . Therefore, ACE inhibitors are a major class of anti- Involvement of RAS in elevation of BP was reported hypertensive drugs. Captopril, chemical name, was for the first time by Tigerstedt and Bergman7, who have the first orally active ACE inhibitory antihypertensive shown that the saline extract of kidney contains some drug, discovered in 1977. Since then, a number of such vasopressor (material that increases BP) activity. It was drugs have been synthesized. Enzyme-inhibitor bound named ‘renin’ as it was extracted from kidney. In 1940s, crystal structural studies reveal a great deal of under- Braun-Mendez and co-workers8 discovered that renin standing about the interactions of the inhibitors at the catalyses the formation of the actual pressor agent, the active site of ACE. This can be helpful in the rational ‘angiotensinogen’ (also called hypertensinogen).