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  Anti-hypertensive molecules and process for preparation thereofUSPTO Application #: 20060183691Title: Anti-hypertensive molecules and process for preparation thereof Abstract: The present invention relates to novel anti-hypertensive molecules. The present invention also provides a process for the preparation of novel antihypertensive molecules. The present invention particularly relates to the preparation of novel Angiotensin Converting Enzyme Inhibitors (ACEI) with prolonged activity. ACE inhibitors play an important role in Renin-Angiotensin-Aldosteron system (RAAS) by inhibiting the activity of Angiotensin Converting Enzyme (ACE) and therefore are used to regulate blood pressure. ACE inhibitors synthesized by the process of present invention have a peptide moiety and nonpeptide moiety. ACE inhibitors, synthesized by this present invention, show enhanced bioavailability and fewer side effects. (end of abstract)
Agent: Ladas & Parry - New York, NY, US Inventors: Santosh Pasha, Qadar Pasha, Kashif Hanif, Mahesh Chand Pavar USPTO Applicaton #: 20060183691 - Class: 514018000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 3 Or 4 Peptide Repeating Units In Known Peptide Chain The Patent Description & Claims data below is from USPTO Patent Application 20060183691. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention relates to novel anti-hypertensive molecules. The present invention also provides a process for the preparation of novel antihypertensive molecules. The present invention particularly relates to the preparation of novel Angiotensin Converting Enzyme Inhibitors (ACEI) with prolonged activity. ACE inhibitors play an important role in Renin-Angiotensin-Aldosteron system (RAAS) by inhibiting the activity of Angiotensin Converting Enzyme (ACE) and therefore are used to regulate blood pressure. ACE inhibitors synthesized by the process of present invention have a peptide moiety and nonpeptide moiety. ACE inhibitors, synthesized by this present invention, show enhanced bioavailability and fewer side effects. BACKGROUND OF THE INVENTION [0002] Hypertension has assumed the form of a grave problem all over the world. In US 23% people are suffering from hypertension. Over three-quarters of women aged 75 or over and 64% of men aged 75 or over have hypertension. (Health, United States, 2002, Table 68). Annually, hypertension cause 23,761 deaths and there are 8.6 deaths per 100,000 population in 2000 (National Vital Statistics Report, Vol. 50, Nc. 15). [0003] In India, it has been estimated that 10-20% people suffer fom hypertension and with increasing urbanization, problem is compounding. Even in India, According to analysis, the prevalence of Hypertension among adults in India is 11%. There is increasing trend in the prevalence of hypertension especially of systolic level. The incidence is more in urban than in rural population. Prevalence is slightly more in women (Gupta, 1997). Cardiovascular deaths in India are estimated to be 2.5 million per year and by 2020 it will be the leading cause of death (Enas et al, 1996). This provides window to our future as we urbanize and adopt unhealthy life styles. Angiotensin Converting Enzyme: Its Physiology [0004] In the development of blood pressure Renin Angiotensin Aldosteron System (RAAS) plays a major role (Petrillo et al, 1982). It interacts with Kallikrein-Kinin-Prostaglandin System (KKP) to regulate blood pressure. ACE, as it is well known, plays a pivotal role in both the system and helps in keeping homeostasis in blood pressure. The key components of RAAS include Renin, Angiotensinogen, Angiotensin Converting Enzyme, Angiotensin-I, Angiotensin-II & Aldosterone. [0005] Increased ACE activity has also been liked to the hypertrophy of endothelial cells in vasculature by decreasing apoptosis. It causes the narrowing of lumen of vessels, which results in increased blood pressure. High ACE activity also contributes to oxidative stress. [0006] Kallikrein-Kinin-Prostaglandin is an alternative blood controlling system (FIG. 1) which is influenced by ACE. Kallikrein is a serine protease glycoprotein synthesized in liver. It acts upon kininogens producing Bradykinin. Bradykinin synthesizes prostaglandins and nitric oxide (NO) that cause the relaxation of smooth muscles leading to a decrease in blood pressure. Angiotensin converting enzyme degades Bradykinin thus augmenting the blood pressure (Bhoola et al, 1999). Interaction of Substrate of Angiotensin Converting Enzyme with Its Active Site [0007] Angiotensin converting enzyme (ACE) plays an important role in both above-mentioned systems. [0008] Angiotensin converting enzyme (MW 150-180 KD) is a membrane bound glycoprotein (Ehlers et al, 1989). It has two homologous domain: N-domain and C-domain. It is a Zn metalloprotease (Ehlers et al, 1989) and removes a dipeptide (His-Leu) from C-terminal of Ang-I (FIG. 2) and converting it to Ang-II, which is a potent vaso-constrictor. The active site of ACE has subsites S.sub.1, S.sub.1' and S.sub.2'. The substrate of ACE, Angiotensin-I, makes hydrophobic interaction with subsites S.sub.1, S.sub.1', S.sub.2'. While Zn.sup.2+ & its coordinated-water molecule are present in a fourth subsite. The substrate gets oriented in such a way that it interacts with zinc-coordinated water molecule as shown in the FIG. 2. The glutamate polarizes and activates water molecule to hydrolyze Angiotensin-I into Angiotensin-II and a dipeptide. Increased ACE activity leads to enhanced production of Ang-II and degradation of bradykinin leading to increased BP. Inhibition of ACE [0009] From above, it can be concluded that ACE by regulating blood pressure is the hub of RAAS and KKP. So it may be deduced that molecules that can reduce ACE activity can be used to counter hypertension because inhibition of ACE leads to two major effects: [0010] (1) Decrease in the conversion of angiotensin I to angiotensin II diminishes the effect of RAAS and thus relaxing the smooth muscles and reduce the production of aldosterone result in decrease of blood volume and blood pressure (Giudicelli et al, 1995). [0011] (2) Decrease in bradykinin degradation in KEP system. Bradykinin, when interacts with B2 receptors at endothelial cells, causes the release of endothelium-derived relaxing factors like nitric oxide (NO) and prostaglandin-prostacyclin which cause relaxation of smooth muscles leading to a decrease in BP (Giudicelli et al, 1995). New Aspects of Inhibition of ACE [0012] Recent reports suggest that advantages of ACE inhibition go beyond its conventional roles because ACEIs [0013] (1) Decrease in hypertrophy that may decline the chances of atherosclerosis (Chobanian et al, 1990). [0014] (2) Decrease in oxidative stress by reducing the formation of superoxide anions (Munzel and Keaney, 2001) [0015] (3) Decrease in tissue factor activity that can prevent the development of atherosclerosis (Napoleone et al, 2000). [0016] (4) Decrease in ACE activity can increase the level of Ac-SDKP and it can be used as anti cancer therapy (Azizi et al, 1996). [0017] In view of the above-mentioned roles of ACE inhibitors in various disorders, several groups of researchers are engaged in developing drug targets as angiotensin converting enzyme inhibitors. Current Status of Hypertension Therapies: Angiotensin Converting Enzyme Inhibitors (ACEIs) [0018] Several vasodilating agents have been synthesized in treatment of congestive heart failure and hypertension. Nitrates like isosorbide mononitrate and glyceryl trinitrates are used to counter hypertension (Winbury and Gabel, 1967) but they have a short duration of action (Cobh, Johnson and Ziesche et al, 1991). A diuretic like thiazide increases the excretion of water and along with it sodium. A decrease in sodium leads to hypovolumia resulting in decreased BP. One of the main shortcoming of diuretics is hypokalemia (Brater, 1998). Ca.sup.+ plays an important role in muscle contraction. Ca.sup.+ channel blockers inhibit influx of Ca.sup.+ and do not let the blood pressure rise (Weiner, 1994). Side effects of headache, dizziness and flushing along with peripheral edema are most prominent with Ca channel blockers (Psaty et al, 1995). .beta.-blockers are also among the front line therapy for hypertension. They block the sympathic beta-receptors, which prevent sympathic simulation of heart rate and cardiac metabolism. Side effects of Beta-blockers are light-headedness, postural hypotension, cold extremities, gastric upset with heartburn, diarrhea and impotence (Quyyumi et al, 1984). [0019] Renin-Angiotensin-Aldosteron System plays the pivotal in development of hypertension. The main acting agent of this system is Ang II, which is a potent vasoconstrictor. There are two main strategies that do not let the Ang II elicit its vasoconstrictive effects. First is AT1 receptor antagonist, which do not let Ang II bind to its AT1 receptors (Goodfriend et al, 1996). Second therapy dealing with RAAS is Angiotensin Converting Enzyme Inhibitors. These inhibitors competitively bind to the active site of ACE and do not let natural substrates (Ang I &Bradykinin) bind to the active site. Captoprils, Enalpril are main ACE inhibitor. [0020] ACEIs are the most important among the drugs controlling hypertension. All the drugs currently available in the market have a more or less similar mode of action. These drugs inhibit the activity of ACE as depicted in the FIG. 1 that leads to decreased formation of Ang II reducing BP. [0021] The main drugs currently available in the market are captopril, enalpril, fosinopril, ramipril and lisinopril. [0022] Captopril is a derivative of proline and D-2-Methyle-3-mercaptopropionic acid whose SH group efficiently interacts with Zn in active site and replaces the water molecule. (Cushman and Ondetti, 1991). [0023] Enalpril has proline and alanine derived moiety whose COO.sup.- group interacts with Zn in active site. It is a prodrug that is converted by esterase activity in liver to more active enalprilate (Patchett et al, 1980). Continue reading... Full patent description for Anti-hypertensive molecules and process for preparation thereof Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Anti-hypertensive molecules and process for preparation thereof patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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