Editing ACE inhibitor (section)

==History==
{{Main|ACE inhibitors drug design}}
[[Leonard T. Skeggs]] and his colleagues (including [[Norman Shumway]]) discovered ACE in [[blood plasma|plasma]] in 1956.<ref name=Bernstein>{{cite journal | vauthors = Bernstein KE, Ong FS, Blackwell WL, Shah KH, Giani JF, Gonzalez-Villalobos RA, Shen XZ, Fuchs S, Touyz RM | title = A modern understanding of the traditional and nontraditional biological functions of angiotensin-converting enzyme | journal = Pharmacological Reviews | volume = 65 | issue = 1 | pages = 1–46 | date = January 2013 | pmid = 23257181 | pmc = 3565918 | doi = 10.1124/pr.112.006809 }}</ref> It was also noted that those who worked in banana plantations in South-western Brazil collapsed after being bitten by a [[pit viper]], leading to a search for a blood pressure lowering component in its venom.<ref name="Aung2012">{{Cite book| vauthors = Myat A, Gershlick AH, Gershlick T |chapter-url=https://books.google.com/books?id=DDmYywOVlToC&pg=PA286|title=Landmark Papers in Cardiovascular Medicine |date=2012|publisher=[[Oxford University Press]]|isbn=978-0-19-959476-4|location=Oxford|pages=2286–287|language=en|chapter=17. Systemic arterial hypertension|lccn=2012940771}}</ref> Brazilian scientist [[Sérgio Henrique Ferreira]] reported a [[Teprotide|bradykinin-potentiating factor]] (BPF) present in the venom of ''[[Bothrops jararaca]]'', a South American pit viper, in 1965.<ref name="pmid14302350">{{cite journal | vauthors = Ferreira SH | title = A BRADYKININ-POTENTIATING FACTOR (BPF) PRESENT IN THE VENOM OF ''BOTHROPS JARARACA'' | journal = British Journal of Pharmacology and Chemotherapy | volume = 24 | issue = 1 | pages = 163–169 | date = February 1965 | pmid = 14302350 | pmc = 1704050 | doi = 10.1111/j.1476-5381.1965.tb02091.x }}</ref> Ferreira then went to [[John Vane]]'s laboratory as a postdoctoral fellow with his already-isolated BPF. The conversion of the inactive angiotensin I to the potent angiotensin II was thought to take place in the plasma. However, in 1967, [[Kevin K. F. Ng]] and [[John R. Vane]] showed plasma ACE is too slow to account for the conversion of angiotensin I to angiotensin II ''in vivo''. Subsequent investigation showed rapid conversion occurs during its passage through the pulmonary circulation.<ref name="Kevin">{{cite journal | vauthors = Ng KK, Vane JR | title = Conversion of angiotensin I to angiotensin II | journal = Nature | volume = 216 | issue = 5117 | pages = 762–766 | date = November 1967 | pmid = 4294626 | doi = 10.1038/216762a0 | s2cid = 4289093 | bibcode = 1967Natur.216..762N }}</ref>

Bradykinin is rapidly inactivated in the circulating blood, and it disappears completely in a single pass through the pulmonary circulation. Angiotensin I also disappears in the pulmonary circulation because of its conversion to angiotensin II. Furthermore, angiotensin II passes through the lungs without any loss. The inactivation of bradykinin and the conversion of angiotensin I to angiotensin II in the lungs was thought to be caused by the same enzyme.<ref name="Kevin2">{{cite journal | vauthors = Ng KK, Vane JR | title = Fate of angiotensin I in the circulation | journal = Nature | volume = 218 | issue = 5137 | pages = 144–150 | date = April 1968 | pmid = 4296306 | doi = 10.1038/218144a0 | s2cid = 4174541 | bibcode = 1968Natur.218..144N }}</ref> In 1970, Ng and Vane, using BPF provided by Ferreira, showed the conversion is inhibited during its passage through the pulmonary circulation.<ref name="Kevin3">{{cite journal | vauthors = Ng KK, Vane JR | title = Some properties of angiotensin converting enzyme in the lung in vivo | journal = Nature | volume = 225 | issue = 5238 | pages = 1142–1144 | date = March 1970 | pmid = 4313869 | doi = 10.1038/2251142b0 | s2cid = 4200012 | bibcode = 1970Natur.225.1142N }}</ref>

BPFs are members of a family of peptides whose potentiating action is linked to inhibition of bradykinin by ACE. Molecular analysis of BPF yielded a nonapeptide BPF [[teprotide]] (SQ 20,881), which showed the greatest ACE inhibition potency and hypotensive effect ''in vivo''. Teprotide had limited clinical value as a result of its peptide nature and lack of activity when given orally. In the early 1970s, knowledge of the structure-activity relationship required for inhibition of ACE was growing. [[David Cushman]], [[Miguel Ondetti]] and colleagues used peptide analogues to study the structure of ACE, using carboxypeptidase A as a model. Their discoveries led to the development of captopril, the first orally-active ACE inhibitor, in 1975.<ref>{{cite journal | vauthors = Cushman DW, Ondetti MA | title = History of the design of captopril and related inhibitors of angiotensin converting enzyme | journal = Hypertension | volume = 17 | issue = 4 | pages = 589–592 | date = April 1991 | pmid = 2013486 | doi = 10.1161/01.HYP.17.4.589 | s2cid = 30766421 | doi-access = free }}</ref>

Captopril was approved by the United States [[Food and Drug Administration]] in 1981.<ref>{{Cite web |title=Drugs@FDA: FDA-Approved Drugs |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=018343 |access-date=2023-09-29 |website=www.accessdata.fda.gov |language=en}}</ref> The first nonsulfhydryl-containing ACE inhibitor, enalapril, was approved four years later.<ref>{{Cite web |title=Drugs@FDA: FDA-Approved Drugs |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=018998 |access-date=2023-09-29 |website=www.accessdata.fda.gov |language=en}}</ref> At least 8 other ACE inhibitors have since been marketed.<ref>{{cite journal | vauthors = Bicket DP | title = Using ACE inhibitors appropriately | language = en-US | journal = American Family Physician | volume = 66 | issue = 3 | pages = 461–468 | date = August 2002 | pmid = 12182524 | url = https://www.aafp.org/pubs/afp/issues/2002/0801/p461.html }}</ref>

In 1991, Japanese scientists created the first milk-based ACE inhibitor, in the form of a fermented milk drink, using specific cultures to liberate the [[tripeptide]] [[isoleucine]]-[[proline]]-proline (IPP) from the dairy protein. [[Valine]]-proline-proline (VPP) is also liberated in this process—another milk tripeptide with a very similar chemical structure to IPP. Together, these peptides are now often referred to as [[lactotripeptides]]. In 1996, the first human study confirmed the blood pressure-lowering effect of IPP in fermented milk.<ref>{{cite journal | vauthors = Hata Y, Yamamoto M, Ohni M, Nakajima K, Nakamura Y, Takano T | title = A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects | journal = The American Journal of Clinical Nutrition | volume = 64 | issue = 5 | pages = 767–771 | date = November 1996 | pmid = 8901799 | doi = 10.1093/ajcn/64.5.767 | doi-access = free }}</ref> Although twice the amount of VPP is needed to achieve the same ACE-inhibiting activity as the originally discovered IPP, VPP also is assumed to add to the total blood pressure lowering effect.<ref name="pmid7673515">{{cite journal | vauthors = Nakamura Y, Yamamoto N, Sakai K, Takano T | title = Antihypertensive effect of sour milk and peptides isolated from it that are inhibitors to angiotensin I-converting enzyme | journal = Journal of Dairy Science | volume = 78 | issue = 6 | pages = 1253–1257 | date = June 1995 | pmid = 7673515 | doi = 10.3168/jds.S0022-0302(95)76745-5 | doi-access = free }}</ref>
Since the first lactotripeptides discovery, more than 20 human clinical trials have been conducted in many different countries.<ref name="pmid19061526">{{cite journal | vauthors = Boelsma E, Kloek J | title = Lactotripeptides and antihypertensive effects: a critical review | journal = The British Journal of Nutrition | volume = 101 | issue = 6 | pages = 776–786 | date = March 2009 | pmid = 19061526 | doi = 10.1017/S0007114508137722 | doi-access = free }}</ref>