Inhibitor vasopeptidase

Mohnaro G, Rouleau J-L, Adam A. Vasopeptidase inhibitors a new class of dual zinc metallopepti-dase inhibitors for cardiorenal therapeutics. Curr Opin Pharmacol 2002 2 131-41. 

In addition, a new class of drugs, termed vasopepti-dase inhibitors, inhibit the enzymatic activity of ACE and neutral endopeptidase, the enzyme responsible for the breakdown of natriuretic peptides. The end result is a reduction in the synthesis of angiotensin II and an increase in the circulating level of natriuretic peptides such as ANP. Omapatrilat, a vasopeptidase inhibitor, is under study for the treatment of hypertension and congestive heart failure. 

Corti R et al. Vasopeptidase inhibitors A new therapeutic concept in cardiovascular disease Circulation 2001 104 1856-1892. 

Vasopeptidase inhibitors are a new class of cardiovascular drugs that inhibit two metalloprotease enzymes, NEP 24.11 and ACE. They thus simultaneously increase the levels of natriuretic peptides and decrease the formation of Ang II. As a result, they enhance vasodilation, reduce vasoconstriction, and increase sodium excretion, in turn reducing peripheral vascular resistance and blood pressure. 

Recently developed vasopeptidase inhibitors include omapatrilat, sampatrilat, and fasidotrilat. Omapatrilat, which has received the most attention, lowers blood pressure in animal models of hypertension as well as in hypertensive patients, and improves cardiac function in patients with heart failure. Unfortunately, omapatrilat causes a significant incidence of angioedema in addition to cough and dizziness and has not been approved for clinical use. 

Worthley MI, Corti R, Worthley SG Vasopeptidase inhibitors Will they have a role in clinical practice Br J Clin Pharmacol 2004 57 27. [PMID 14678337]... 

L-6-Hydroxynorleucine, a different key chiral intermediate used for synthesis of the vasopeptidase inhibitor Omapatrilat (Vanlev ), was prepared in 89% yield and > 99% optical purity by reductive amination of 2-keto-6-hydroxyhexanoic acid using glutamate dehydrogenase from beefliver (Hanson, 1999) (Figure 13.22). In an alternative process, racemic 6-hydroxynorleucine produced by hydrolysis of 5-(4-hydroxybutyl)hydantoin was treated with D-amino acid oxidase to prepare a mixture containing 2-keto-6-hydroxyhexanoic acid and L-6-hydroxynorleucine followed by the reductive amination procedure to convert the mixture entirely to L-6-hydroxynorleucine, with yields of 91-97% and optical purities of > 99%. 

L. W. Parker, and J. J. Venit, Biocatalytic preparation of a chiral synthon for a vasopeptidase inhibitor enzymatic conversion of N2-[N-phenylmethoxy)carbo-nyl] L-homocysteinyl]- l-lysine (1,1 J-disulfide to 4S-(4/,71,10aJ)]-l-octahydro-5-oxo-4-[phenylmethoxy)carbonyl]amino]-7H-pyrido-[2,l-b][l,3]thiazepine-7-carboxylic add methyl ester by a novel l -lysine e-aminotransferase, Enzyme Microb. Technd. 2000, 27, 376-389. 

Administration of BNP as nesiritide (see Chapter 13 Drugs Used in Heart Failure) in patients with severe heart failure increases sodium excretion and improves hemodynamics. However, the peptide has to be given by constant intravenous infusion. A more promising approach may be the use of drugs that inhibit the neutral endopeptidase responsible for the breakdown of ANP. This is discussed below under Vasopeptidase Inhibitors. 

Recently developed vasopeptidase inhibitors include omapatrilat, sampatrilat, and fasidotrilat. 

L-6-Hydroxynorleucine (1) (Fig. 1) is a chiral intermediate that is useful for the synthesis of a vasopeptidase inhibitor now in clinical trial and for the synthesis of C-7-substituted azepinones as potential intermediates for other antihypertensive... 

Figure 1 Preparation of chiral synthon for vasopeptidase inhibitor enzymatic synthesis of L-6-hydroxynorleucine (1) using glutamate dehydrogenase.

S)-2-Amino-5-(l,3-dioxolan-2-yl)-pentanoic acid [allysine ethylene acetal (4)] is one of three building blocks used for an alternative synthesis of omapatrilat, a vasopeptidase inhibitor [13,14], It has previously been prepared in an eight-step synthesis from 3,4-dihydro-2H-pyran [23],... 

The vasopeptidase inhibitor omapatrilat is a pure stereoisomer and its systematic name is (4S,7S,10aS)-5-oxo-4- [(2S)-3-phenyl-2-sulfanylpropan-oyl]amino octahydropyrido[2,l-fo] [ 1,3]thiazepine-7-carboxylic acid. Draw the structural formula of this compound with complete specification of the... 

Pfister, M. Martin, N.E. Haskell, L.P. Barrett, J.S. Optimizing dose selection with modeling and simulation application to the vasopeptidase inhibitor Ml00240. J. Clin. Pharmacol. 2004, 44, 621-631. 

The preparation of 2 by enzymatic reductive amination provides the single enantiomer of the amino acid acetal by a shorter route than the previously published eight-step synthesis of racemic ally sine ethylene acetal. " Unlike the previously described route, the enzymatic route does not reqnire addition and removal of protecting groups, and therefore gives better atom economy. The synthesis of keto acid 1 and enzymatic reductive amination to 2 as described proved to be suitable for the preparation of the large qnantities of the vasopeptidase inhibitor needed for clinical trials. 

---