Factor Xa is a serine protease that has a critical role in the blood coagulation cascade by ultimately regulating the production of thrombin. There is now ample evidence for the role of Factor Xa inhibitors as anticoagulants and they represent potential new therapeutic agents for the treatment and prevention of arterial and venous thrombosis. During the past five years, research in the field of Factor Xa inhibitors has been marked with enormous efforts to identify highly potent, selective and orally-active agents. This research has led to the discovery of a number of clinical candidates that are currently progressing at different stages of drug development. This review examines the patent and scientific literature during the period 2000 – 2005.
Two novel routes have been developed to the (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one 2 of the CGRP receptor antagonist clinical candidate telcagepant (MK-0974, 1). The first employs a ring-closing metathesis of the styrene 7 as the key reaction, while the second makes use of a highly diastereoselective Hayashi−Miyaura Rh-catalyzed arylboronic acid addition to nitroalkene 16. The latter route has been implemented to produce multigram quantities of telcagepant for extensive preclinical evaluation.
R 58 735, a benzthiazole derivative, is a potent antihypoxic agent with anticonvulsant properties. As an antihypoxic drug, it was more potent than any other reference substance in hypobaric hypoxia in mice and in histotoxic dysoxia and nitrogen hypoxia in rats. In the nitrogen hypoxia test, R 58 735 was equipotent in males and females, and the p.o.\i.v. ratio varied from 2.8 to 2.6. The antihypoxic activity of orally administered R 58 735 latested more than 8, but less than 24 hr. The anticonvulsant profile of R 58 735 resembled that of flunarizine, i.e., blockade of the tonic convulsions induced by pentylenetetrazol, allylglycine, or bicuculline, but not of clonic convulsions, except those seen in audiogenic seizureprone mice. In the allylglycine or bicuculline tests, it was more potent than any other reference anticonvulsant. In the bicuculline test, there were no sex-related differences in activity, and the p.o.\s.c. activity ratio was 2.01 in males and 1.74 in females. Following oral administration, the duration of anticonvulsant activity in the bicuculline test was more than 8, but less than 24 hr. In guinea pigs, R 58 735 completely antagonized hypoxia-induced amnesia at a dose of 2.5 mg\kg s.c. Furthermore, it enhanced acquisition of a two-way avoidance task over a broad dose range (0.63–20 mg\kg) in rats.
Drug Development Research
Volume 8, Issue 1-4, pages 373–380, May - August 1986
Bowman–Birk inhibitor analogues containing 2, 3 and 4-carbon analogues of the natural disulfide were synthesised via solid phase microwave-assisted RCM and found to have Ki values against chymotrypsin in the low to sub-micromolar range, the best replacement for the disulfide arising from the linkage by RCM of two L-homoallylglycine residues.
Chiral Intermediates
Hybiochem takes its specialty amino acids "downstream" to the manufacture of many complex chiral intermediates. Multiple adjacent chiral centers, required for an increasing number of developmental drugs, can be accessed through amino acid derivative chemistry.
Specialty Amino Acids
Specialty amino acids, their derivatives, and small peptides continue to gain importance in drug development. Reliable, cost-effective commercial supply of these intermediates is crucial for a successful drug launch.
Protected Amino Acids
Both solid phase and solution phase peptide syntheses are demanding a growing array of protected amino acids. These peptide syntheses require amine protection, side-chain protection, and often acid activation or protection. The addition order of the protecting groups can have a significant influence on both the cost and quality of a particular derivative.
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