Captopril Triumph.

By Telesphory Wamara And Sarafina Msigwa

The deadly South American pit viper (Bothrops jararaca) is known for its deadly venom ,it kills its prey through injection of venom, once injected in prey the venom has remarkable ability of causing high drop in blood  pressure consequently causing instant death. The venom that produces this result solves the snake’s dietary problem promptly because it can now catch up with its immobilized victim and consume it. A few insightful scientists understanding these considerations recognized the potential value of snake venom to control malignant blood pressure if administered carefully to sufferers. The design of the antihypertensive drug captopril, a clinically important and potent reversible inhibitor of ACE, is an example of one of the early endeavors and successes of a rationally designed enzyme inhibitor, and one among of its design ideas comes from the pit viper snake venom.

By about 1965 it was found that the active principles in the venom of the South American pit viper Bothrops jararaca were a mixture of closely related peptides that inhibit angiotensin-converting enzyme. The question, then, was whether medicinal chemists and physicians could utilize this mechanism to control hypertension through the crafty application of drugs based on the venom. Unfortunately, the active constituents in the venom, being peptides, must be injected in order to work. The snake has no problem with this. Physicians and patients, however, would. As noted, most hypertensive individuals do not perceive unpleasant symptoms from their disease until their disease is far advanced. Consequently, there would be little motivation to take a lifelong series of injections when generally feeling rather fit. Under these circumstances, the treatment would be more apparently troublesome than the disease. Consequently, successful drugs for this indication would have to be taken orally and not have unpleasant side effects or they would not be used. Angiotensin-converting enzyme (ACE) is a carboxypeptidase having a zinc ion as a cofactor and is involved in the renin-angiotensin cascade of blood pressure control, Carboxypeptidase A is a hydrolytic enzyme naturally isolated from bovine pancreas. A nonapeptide, teprotide, isolated from the pit vipers venom had the greatest in vivo potency in inhibiting ACE and was shown to consistently lower blood pressure in patients with essential hypertension. Scientists used teprotide and other peptide analogues to provide an enhanced understanding of the enzymatic properties of ACE. Using knowledge of substrate-binding specificities and the fact that ACE has properties similar to those of pancreatic carboxypeptidases, these researchers developed a hypothetical model of the enzyme active site. Carboxypeptidase A, like ACE, is a zinc-containing exopeptidase. The development of captopril and other orally active ACE inhibitors began with the observation that D-2-benzylsuccinic acid was an extremely potent inhibitor of carboxypeptidase A. The binding of this compound to carboxypeptidase A  is very similar to that seen for substrates with the exception that the zinc ion binds to a carboxylate group instead of the labile peptide bond. It was proposed that this compound is a by-product analogue that contains structural features of both products of peptide hydrolysis. Most of the structural features of the compound are identical to the terminal amino acid of the substrate , whereas the additional carboxylate group is able to mimic the carboxylate group that would be produced during peptide hydrolysis. Applying this concept to the hypothetical model of ACE described above resulted in the synthesis and evaluation of a series of succinic acid derivatives . Because proline was present as the C-terminal amino acid in teprotide as well as in other potent, inhibitory snake venom peptides, it was included in the structure of newly designed inhibitor

                   Series of modifications

 The first inhibitor to be synthesized and tested was succinyl-L-proline . This compound proved to be somewhat disappointing. Although it provided reasonable specificity for ACE, it was only approximately 1/500 as potent as teprotide. Substitution of other amino acids in place of proline produced compounds that were even less potent, hence all subsequent SAR studies were conducted using analogues of L-proline.  The addition of a methyl group to the 2 position of succinyl-L-proline to mimic the amino acid side chain, R2, of the substrate enhanced activity but only marginally. D-2-Methylsuccinyl-L-proline had effects similar to teprotide   but was still only 1/300 as potent. The D-isomer, rather than the L-isomer normally seen for amino acids, was necessary because of the isosteric replacement of an NH2 with a CH2 present in succinyl-L-proline. A comparison of the R2 group of the substrate   with the methyl group of D-2-methylsuccinyl-L-proline, illustrates that this methyl group occupies the same binding site as the side chain of an L-amino group  .One of the most important alterations to succinyl-L-proline was the replacement of the succinyl carboxylate with other groups having enhanced affinity for the zinc atom bound to ACE. Replacement of this carboxylate with a sulfhydryl group produced 3-mercaptopropanoylL-proline .This compound was very potent than succinyl-L-proline. Additionally, it is 10- to 20-fold more potent than teprotide   in inhibiting contractile and vasopressor responses to angiotensin I. Addition of a 2-D-methyl group further enhanced activity. The resulting compound was captopril  a competitive inhibitor of ACE and was the first ACE inhibitor to be marketed.