Discovery of Aliskiren (Renin Inhibitor)

Aliskiren (Tekturna) is the first orally active renin inhibitor approved for clinical use. It was approved by the US Food and Drug Administration and the European Medicines Agency in 2007 for the treatment of Primary hypertension.
It was developed by Ciba-Geigy (now Novartis).

1. DISCOVERY OF ALISKIREN SAKEEL AHMED (PhD Scholar) Department of Pharmacology (NIPER, Mohali)

2. ALISKIREN A liskiren (Tekturna) is the first orally active renin inhibitor approved for clinical use. It was approved by the US Food and Drug Administration and the European Medicines Agency in 2007 for the treatment of Primary hypertension. Aliskiren has shown efficacy as a monotherapy. Combining Aliskiren with other antihypertensive drugs, ACE inhibitors, ARBs, calcium-channel blockers and diuretics It was developed by Ciba-Geigy (now Novartis) . 2

3. RENIN ANGIOTENSIN SYSTEM ( Matthew J. Munro et al. , 2017) 3

4. CLASSIFICATION OF RENIN INHIBITORS 1. First Generation : Example: Enalikiren ( CGP29287) 2. Second Generation: Example: CGP38560 3. Third Generation: Example: Aliskiren 4

5. The peptidomimetic approach was unsuccessful. 5

6. COMPUTATIONAL APPROACH FOR ALISKIREN Figure: 3D model of the enzyme and docking of CGP38560. Figure: The predicted bioactive conformation of CGP38560. 6

7. The drug design strategy based on the predicted bioactive conformation of CGP38560 7

8. 8

9. Four compounds representing a third generation of renin inhibitors: the THQ, phenoxy, indole and salicylamide leads From μ M to nM biological activities in the phenoxy series. 9

10. Figure: Superimposition of the four lead compounds 10

11. Figure: The complex with Aliskiren and the S3sp sub-pocket Figure: Comparison between the predicted bioactive conformation of CGP38560 (red) and the one observed experimentally (black) 11

12. Aliskiren 12

13. The Renin Project in perspective. 14

14. REFERENCES Cohen, N. C. and Park, T. (2007) ‘Structure-Based Drug Design and the Discovery of Aliskiren ( Tekturna Ò ): Perseverance and Creativity to Overcome a R & D Pipeline Challenge ‡’, pp. 557–565. doi : 10.1111/j.1747-0285.2007.00599.x. Imanishi , T., Tsujioka , H. and Akasaka, T. (2009) ‘Hypertension Management and End Organ Protection : Focus on Aliskiren’, pp. 321–331. 15