Why target Renin
Renin is an enzyme that plays a major role in the Renin-Angiotensin System, a regulatory system in the body, which is responsible to maintain homeostasis of blood pressure. The enzyme belongs to the family of aspartic proteases and is responsible for the conversion of inactive angiotensinogen to angiotensin I (Ang I). Angiotensin I by itself is inactive. However, when acted upon by angiotensin converting enzyme (ACE) it gets converted to angiotensin II, which is active and is responsible for most of the pressor effects. Conversion of angiotensinogen to angiotensin I is the rate determining step of the system. The catalytic role played by renin is thus crucial in mediating blood pressure by the Renin-Angiotensin System.
Development of Renin Inhibitors
Direct renin inhibition offers another weapon in the arsenal against hypertension. Early inhibitors of renin were monoclonal antibodies, which were excellent probes of enzyme function. However, they were in no ways suitable for use as medication as most were immunogenic and had to be administered via parenteral route. Transition state analogs in the form of statins were first synthesized and were found to be potent inhibitors of renin. However, they had drawbacks because of their peptide like nature and their lack of oral bioavailability. Modifications of these statins led to the development of CGP38560, a compound with reduced peptidic character and of smaller size (MW=730). Optimization of this compound by Novartis led to the development of Aliskiren- the only direct renin inhibitor which is clinically used as an antihypertensive drug. 
Aliskiren, is a first-in-class oral renin inhibitor, developed by Novartis in conjunction with the biotech company Speedel. It was approved by the US Food and Drug Administration in 2007. It is an octanamide, is the first known representative of a new class of completely non-peptide, low-molecular weight, orally active transition-state renin inhibitors. Designed through the use of molecular modeling techniques, it is a potent and specific in vitro inhibitor of human renin (IC50 in the low nanomolar range), with a plasma half-life of ≈24 hours. Aliskiren has good water solubility and low lipophilicity and is resistant to biodegradation by peptidases in the intestine, blood circulation, and the liver. It was approved by the United States FDA on 6 March 2007, and for use in Europe on 27 August 2007. Its trade name is Tekturna in the USA, and Rasilez in the UK.
While Novartis was developing inhibitors by modification of the peptide-like inhibitors of renin, Hoffman-La Roche started developing renin inhibitors, which were completely different in structure, having a piperidine ring. Screening of the Roche compound libraries led to the identification of rac-2(molecule a) (piperidine structure) which was selective in inhibiting renin over other aspartic proteases. Hoffman-La Roche pursued the development of these compounds until 2001 advancing to pre-clinical stage. Based on the piperidine structure, Pfizer pursued the task of designing ketopiperazine-based renin inhibitors which have shown greater potential(molecule b). More recently a new series of renin inhibitors based on the ketopiperazine structure was developed by Actelion Pharmaceuticals. These molecules have a 3,9-diazabicyclo[3.3.1] nonene group in place of the ketopiperazine group (molecule c). Another group of chemists from Vitae Pharmaceuticals has developed orally bioavailable alkyl amines based solely on a computational structure-based design (molecule d).
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- Renin inhibitor aliskiren leads to dose-dependent blood pressure reductions - medicalnewstoday.com.
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- Direct Renin Inhibitors Presentation
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