Medicinal chemistry poster highlights.
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Biomedical subjects
P Agathangelou
Publications and source records attributed to P Agathangelou.
Combinatorial chemistry applications.
In the last decade, combinatorial chemistry has emerged as an indispensable tool for lead compound generation and optimization for every major pharmaceutical company. Presentations in this symposium focused on various approaches, advances and successes in this area of drug discovery/optimization, as well as specific cases to exemplify important issues faced by individual companies.
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Division of Medicinal Chemistry--endothelins.
The endothelins are a family of three potent vasoactive peptides, ET-1, -2 and -3, which comprise 21 amino acids and contain two disulfide bridges between cysteine residues. They were originally isolated from human vascular endothelial cells. Two endothelin receptor subtypes, A and B (ETA and ETB, respectively) have also been identified, although their function still requires further clarification. A brief overview of this field, particularly in terms of the pharmacology and physiology of endothelins, was given by a number of the speakers, who also focused on the recent developments and discoveries within their own projects.
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Division of Medicinal Chemistry--general oral session/fellowship awards.
The primary purpose of this session was to recognize the outstanding achievements in the field of medicinal chemistry. The ACS award for Creative Invention went to researchers at Merck and Co Inc, who successfully developed Crixivan (indinavir, L-735524), an HIV-1 protease inhibitor, which received FDA approval in record time and is now used by over 300,000 patients worldwide. A former Merck scientist, John Baldwin (Pharmacopeia Inc, USA), was honored with the EB Hershberg award for Important Discoveries in Medicinally Active Substances. Dr Hershberg has been at the forefront of drug discovery technologies, such as combinatorial chemistry and rational drug design. During his 30-year career at Merck, he was involved with the Pepcid, Crixivan and Trusopt projects, but eventually left in 1993 when he co-founded Pharmacopeia.
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Division of Carbohydrate Chemistry--recent developments in oligonucleotide therapeutics.
This session from the Carbohydrate Division of the ACS was overviewed by P Dan Cook of ISIS Pharmaceuticals Inc, who described what had already been accomplished in this field, as well as research efforts at his own company. The general message to emerge was that antisense drug discovery and development is very much alive and is progressing rapidly. Particular emphasis was placed on the importance of the pharmacodynamic (ie, absorption, distribution, metabolism and elimination) properties of the new second and third generation therapeutics which are emerging from various sources.
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Viral proteases and phosphorodiesterase inhibitors.
A number of novel drug candidates, which are at different stages of development and various therapeutic targets, mechanisms of action and clinical data were discussed in depth. Crystallographic studies and structures of several viral proteases were outlined and described. AG7088 (Agouron Pharmaceuticals Inc) has been developed as a potent, selective human rhinovirus (HRV)3C protease inhibitor, which has now advanced to phase II trials. Vertex Pharmaceuticals Inc has also made significant progress with a series of non-reversible hepatitis C virus (HCV)inhibitors, which were synthesized by solid-phase methods. The pharmacological profile of CI1018 (Parke-Davis (France)), which is in phase I trials for the treatment of asthma, was described as well as the synthesis of potent back-up compounds, 4-oxo-1-phenyl-3,4,6,7-tetrahydro-(1,2)-diazepino[6,7,1-hi]indoles. Other phosphorodiesterase (PDE)4 inhibitors discussed include: SB207499 (SmithKline Beecham plc), now in phase III trials for chronic obstructive pulmonary disease (COPD); and, RP73401, which was in phase II trials for asthma but has been discontinued.
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