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From Venom to Synthetic Inhibitor a Closer L ook A t Captopril

From Venom to Synthetic Inhibitor a Closer L ook A t Captopril . http://www.latoxan.com/VENOM/SNAKE/Bothrops-jararaca.php. Advanced Organic Chemistry Dr. Clower By: Sam Kennedy. http://www.latoxan.com/VENOM/SNAKE/Bothrops-jararaca.php. Overview. Ace Inhibitors

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From Venom to Synthetic Inhibitor a Closer L ook A t Captopril

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  1. From Venom to Synthetic Inhibitor a Closer Look At Captopril http://www.latoxan.com/VENOM/SNAKE/Bothrops-jararaca.php Advanced Organic Chemistry Dr. Clower By: Sam Kennedy http://www.latoxan.com/VENOM/SNAKE/Bothrops-jararaca.php

  2. Overview • Ace Inhibitors • Renin Angiotensin Aldosterone System • Ace Mechanism & Binding Interaction • Development of Captopril • Captopril Binding/Optimization • Final FDA Approval of Captopril • Captopril Synthesis

  3. ACE Inhibitors • Angiotensin converting enzyme (ACE) catalises the conversion of angiotensin I (A-I) to angiotensin II(A-II) • The ACE activity directly related to hypertension • AngII is the blood pressure regulating hormone • ACE inhibitors are a major class of antihypertensive drugs • Captopril, was the first orally active ACE inhibitory antihypertensive

  4. Renin Angiotensin Aldosterone System http://en.wikipedia.org/wiki/Renin%E2%80%93angiotensin_system

  5. ACE Mechanism Of Action www.york.ac.uk/res/pac/teaching/AsymmSynth%20handouts.pdf

  6. ACE Mechanism & Binding Interactions http://www.4college.co.uk/a/Md/medicine.php

  7. Development of Captopril • How did they design the drug? • From studies of the snake venom, the researchers found that one particular variation of bradykinin, a nine-amino-acid peptide called teprotide • it effectively reduced blood pressure and seemed to have a long-lasting effect. However, it was expensive, and could not be administered orally. • Miguel Ondetti, Bernard Rubin and David Cushman at the at the U.S. drug company Squibb (now Bristol-Myer Squibb) systematically modifying the structure of tetroprideto see what effect it had on blood pressure. • It turned out that the active part was the proline group at the end teprotide • The rest of the molecule helped bind this to the active site in the ACE enzyme.

  8. Development of Captopril Cont. Teprotide Lead http://en.wikipedia.org/w/index.php?title=File:Teprotide.svg&page=1

  9. Development of Captopril Cont. L-Proline marvindraw

  10. Development of Captopril Cont.Succinyl-L-proline

  11. Development of Captopril Cont. Captopril

  12. Final FDA Approval of Captopril • Captopril gained FDA approval on April 6, 1981, • adverse side-effects, cough, rashes, and taste disturbances • Other ACE-inhibitor drugs have been developed based on Captopril's structure

  13. Captopril Binding Interaction/Optimization http://www.4college.co.uk/a/Md/medicine.php

  14. Captopril Through the Baylis-Hillman Reaction Reaction Scheme Reagents and Conditions. a: acryloyl chloride,KOH, H2O-Acetone, 0°,70%; b: aq. CH2O 40%, H 2O, ultrasound, 47%;c: H2, Pd/C, 92% (4:1 diastereomericratio); d: silica gel, 70% of the major isomer; e: SOCl2, THF-H 2O; thenNH4SH/H 2O, 87%. Almeida et al.

  15. Future Directions • Chronic dehydration • Lactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic ''Lactobacillus helveticus'' ACE-inhibiting and antihypertensive functions. • Metabolic pathway of production of ACE

  16. References • 1.Almeida Wanda P. & Feltrin Melissa P. (2006). A Synthesis of Captopril Through a Baylis-Hillman Reaction. Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry. 33 (7), 1141-1146. • 2.Atlas Steven A. (2007). The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacological Inhibition. Supplement to Journal of Managed Care Pharmacy. 13 (S-b), S9-S20. • 3.Bhaskar J. Bhuyan & GovindasamyMugesh. (2011). Angiotensin converting enzyme inhibitors in the treatment of hypertension. Current Science. 101 (7), 881-887. • 4. Cushman David w. & Ondetti miguel A. (1999). Design of angiotensin converting enzyme inhibitors. Nature. 5 (10), 1110-1112. • 5.Cushman David w. & Ondettimiguel A. (1991). History of the design of captopril and related inhibitors of angiotensin converting enzyme. Hypertension. American Heart Association 1991;17:589-92, doi:10.1161/01.HYP.17.4.589 • 6.Mohd Akit et al.. (2011). Structural characterization of angiotensin I-converting enzyme in complex with a selenium analogue of captopril. The FEBS Journal. 278 (1), 3644-3650.

  17. Acknowledgements • Dr. Joshua Parker‎ • Dr. Caroline Clower • Clayton State Biology/ Chemistry Department

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