Benazepril, sold under the brand name Lotensin among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combinations benazepril/hydrochlorothiazide and benazepril/amlodipine.Common side effects include feeling tired, dizziness, cough, and light-headedness with standing. Serious side effects may include kidney problems, low blood pressure, high blood potassium, and angioedema. Use in pregnancy may harm the baby, while use when breastfeeding may be safe. It is an ACE inhibitor and works by decreasing renin-angiotensin-aldosterone system activity.Benazepril was patented in 1981 and came into medical use in 1990. It was created by the chemist Mahesh Desai. It is available as a generic medication. In 2019, it was the 130th most commonly prescribed medication in the United States, with more than 5 million prescriptions. Structure Activity Relationship
Benazepril Hydrochlorides OCh2Ch3 group must be metabolized in order to inhibit the ACE Enzyme to form Benazeprilat, which is the active form of the molecule. The bulky cyclic structure is resistant to hydrolysis. A special note about the molecule is that the nitrogen within the ring makes the bulky cyclic structure especially harder to break down, and can account for the drugs PK profile, in which the duration of action is 24 hours. Medical uses
It is useful for high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure.
Interactions
When combined with intravenous agalsidase alfa or beta, which are recombinant versions of the enzyme α-GalA, migalastat increases tissue concentrations of functional α-GalA compared to agalsidase given alone up to fivefold.Migalastat is not intended to be combined with agalsidase.Migalastat does not inhibit or induce cytochrome P450 liver enzymes or transporter proteins and is therefore expected to have a low potential for interactions with other drugs. Pharmacology
Mechanism of action
Fabry disease is a genetic disorder caused by various mutations of the enzyme α-GalA, which is responsible for breaking down the sphingolipid globotriaosylceramide (Gb3), among other glycolipids and glycoproteins. Some of these mutations result in misfolding of α-GalA, which subsequently fails protein quality control in the endoplasmic reticulum and is decomposed. Lack of functional α-GalA leads to accumulation of Gb3 in blood vessels and other tissues, with a wide range of symptoms including kidney, heart, and skin problems.Migalastat is a potent, orally available inhibitor of α-GalA (IC50: 4 μM). When binding to faulty α-GalA, it shifts the folding behaviour towards the proper conformation, resulting in a functional enzyme provided the mutation is amenable. Molecules with this type of mechanism are called pharmacological chaperones.When the enzyme reaches its destination, the lysosome, migalastat dissociates because of the low pH and the relative abundance of Gb3 and other substrates, leaving α-GalA free to fulfill its function. Depending on the mutation, the EC50 is between 0.8 μM and over 1 mM in cellular models.