Custom Synthesis of beta & gamma Amino Acids including Statine Analogues

Published on 12/08/2014

GABA is a neurotransmitter in the central nervous system of mammals and its deficiency is associated with severe neurological disorders. Statine, a GABA analogue, occurs in several peptide APIs.

Derivatives of gamma-amino acid analogues are of continued vital interest for a variety of applications in medicinal chemistry.

We have a tool box available to offer a broad range of substituted gamma-amino acids and statines on custom synthesis basis.

Background:

Beta and gamma homologues of natural amino acids provide a broad use as building blocks for peptidomimetics and the synthesis of heterocyles. Possessing extra carbons between the amino and carboxylic acid function, this class of compounds have greater potential for structural diversity than their alpha-analogues. Even more, these derivatives are in general more stable to hydrolysis or enzymatic degradation compared to natural amino acids.

Custom Synthesis of substituted beta & gamma Amino Acids including Statine Analogues

GABA and analogues are involved in several biological functions like cell proliferation and migration, and may play a role in cancer, in mucus overproduction in asthma acting on airway epithelial cells. GABA itself is a neurotransmitter in the central nervous system of mammals and its deficiency is associated with severe neurological disorders, such as Parkinson’s and Huntington’s disease.

Custom Synthesis of substituted beta & gamma Amino Acids including Statine Analogues Statine is a gamma amino acid that occurs twice in the sequence of pepstatin, a protease inhibitor that is active against pepsin and other acid proteases, like aspartic acid protease. In this context it has been found that the beta-hydroxy group is important for tight binding and its stereochemistry has a large effect on protease inhibition. A syn diastereomeric position between the amine and hydroxyl groups is essential.

Potential and diversity:

The administration of GABA orally or intravenously is no efficient therapy due to its low lipophilicity, and its poor ability to cross the blood-brain-barrier. Consequently, the design of more lipophilic GABA derivatives capable to cross the BBB, which could inhibit the GABA transaminase, has already been the target of a great number of studies in the past. Already commercially available are derivatives in Vigabatrin^® Baclon^® Pregabalin^®.

Statin is regarded as the key pharmacophore in the renin inhibitor pepstatin isolated from bacteria. Molecules containing these elements inhibit human immunodeficiency virus type 1 (HIV-1) proteinase and other proteases, are active against cathepsin D, virus protease (FIV PR) and are candidates for further drug development in Alzheimer's disease.

GABA, Statine and its analogues are therefore very useful as building blocks with high potential and show that this class of compounds are key structural elements in modern drug design.

Our Tool Box	Achieved Properties
2,2-disubstituted beta-homo-amino acids 2,2-disubstituted gamma-amino acids 3,3-disubstituted gamma-amino acids Statine analogues with side chains of any natural amino acids unusual residues	High structural diversity with novel structures Improved enzymatic stability Modified release properties Superior biological activity Better cell penetration Better chemical stability Enhanced enzymatic stability Fine tuning of solubility and lipohilicity Adjusting isoelectrical point

✔ We have a tool box available to synthesize a large range of beta & gamma Amino Acids including Statine Analogues

> Send us the Inquiry of your derivative! <

Stereoselective synthesis of gamma-amino acids; Mario Ordónez, Carlos Cativiela; Tetrahedron: Asymmetry 2007; 18(1): 3-99. DOI: 10.1016/j.tetasy.2006.12.001.
Amino Acids, Peptides and Proteins in Organic Chemistry. Vol. 1 – Origins and Synthesis of Amino ACids. Edited by Andre B. Hughes; 2011; Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. ISBN: 978-3-527-32096-7; Chapter 13 Synthesis of gamma- and delta-Amino Acids; Andrea Trabocchini, Gloria Menchi, Antonio Guarna; 527-677.
SDZ PRI 053, an orally bioavailable human immunodeficiency virus type 1 proteinase inhibitor containing the 2- aminobenzylstatine moiety. Billich A, Fricker G, Müller I, Donatsch P, Ettmayer P, Gstach H, Lehr P, Peichl P, Scholz D, Rosenwirth B.; Antimicrob Agents Chemother. 1995; 39(7): 1406-13.
Design and synthesis of hydroxyethylene-based peptidomimetic inhibitors of human beta-secretase. Hom RK, Gailunas AF, Mamo S, Fang LY, Tung JS, Walker DE, Davis D, Thorsett ED, Jewett NE, Moon JB, John V.; J Med Chem. 2004; 47(1): 158-64.
Molecular basis for selectivity of high affinity peptide antagonists for the gastrin-releasing peptide receptor. Tokita K, Katsuno T, Hocart SJ, Coy DH, Llinares M, Martinez J, Jensen RT. J Biol Chem. 2001; 276(39): 36652-63.
Mechanism of Inhibition of beta-site amyloid precursor protein-cleaving enzyme (BACE) by a statine-based peptide. Marcinkeviciene J, Luo Y, Graciani NR, Combs AP, Copeland RA. J Biol Chem. 2001; 276(26): 23790-4.
Inhibition of cathepsin D by tripeptides containing statine analogs. Bessodes M, Antonakis K, Herscovici J, Garcia M, Rochefort H, Capony F, Lelièvre Y, Scherman D. Biochem Pharmacol. 1999; 58(2): 329-33.
Statine-containing renin inhibitor. Dissociation of blood pressure lowering and renin inhibition in sodium-deficient dogs. Blaine EH, Schorn TW, Boger J. Hypertension. 1984; 6(2 Pt 2): I111-8.
Anti-AIDS agents 49. Synthesis, anti-HIV, and anti-fusion activities of IC9564 analogues based on betulinic acid. Sun IC1, Chen CH, Kashiwada Y, Wu JH, Wang HK, Lee KH. J Med Chem. 2002; 45(19): 4271-5.