ABSTRACT
Design and synthesis of a series of very potent nonpeptide HIV protease inhibitors are described. The inhibitors are derived from novel high affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere.
Subject(s)
HIV Protease Inhibitors/chemical synthesis , Sulfonamides/chemistry , Cell Line , Drug Design , Humans , Ligands , Models, Chemical , Saquinavir/analogs & derivatives , Saquinavir/chemistryABSTRACT
Analogs of A-98593 (1) and its enantiomer ABT-594 (2) with diverse substituents on the pyridine ring were prepared and tested for affinity to nicotinic acetylcholine receptor binding sites in rat brain and for analgesic activity in the mouse hot plate assay. Numerous types of modifications were consistent with high affinity for [3H]cytisine binding sites. By contrast, only selected modifications resulted in retention of analgesic potency in the same range as 1 and 2. Analogs of 2 with one or two methyl substituents at the 3-position of the azetidine ring also were prepared and found to be substantially less active in both assays.
Subject(s)
Analgesics, Non-Narcotic/chemical synthesis , Analgesics, Non-Narcotic/pharmacology , Azetidines/chemical synthesis , Azetidines/pharmacology , Nicotinic Agonists/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Receptors, Nicotinic/metabolism , Alkaloids/metabolism , Analgesics, Non-Narcotic/metabolism , Animals , Azetidines/chemistry , Azetidines/metabolism , Azocines , Binding Sites , Brain/metabolism , Mice , Nicotinic Agonists/chemistry , Pain Measurement/drug effects , Pyridines/chemistry , Pyridines/metabolism , Quinolizines , Rats , Receptors, Nicotinic/drug effects , Stereoisomerism , Structure-Activity Relationship , TritiumABSTRACT
Design and synthesis of nonpeptidal bis-tetrahydrofuran ligands based upon the X-ray crystal structure of the HIV-1 protease-inhibitor complex 1 led to replacement of two amide bonds and a 10 pi-aromatic system of Ro 31-8959 class of HIV protease inhibitors. Detailed structure-activity studies have now established that the position of ring oxygens, ring size, and stereochemistry are all crucial to potency. Of particular interest, compound 49 with (3S,3aS,6aS)-bis-Thf is the most potent inhibitor (IC50 value 1.8 +/- 0.2 nM; CIC95 value 46 +/- 4 nM) in this series. The X-ray structure of protein-inhibitor complex 49 has provided insight into the ligand-binding site interactions. As it turned out, both oxygens in the bis-Thf ligands are involved in hydrogen-bonding interactions with Asp 29 and Asp 30 NH present in the S2 subsite of HIV-1 protease. Stereoselective routes have been developed to obtain these novel ligands in optically pure form.
Subject(s)
Furans , Furans/chemical synthesis , Furans/pharmacology , HIV Protease Inhibitors/chemical synthesis , HIV Protease/metabolism , Amino Acid Sequence , Aspartic Acid , Binding Sites , Crystallography, X-Ray , Drug Design , Furans/chemistry , HIV Protease/chemistry , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , HIV-1/enzymology , Hydrogen Bonding , Ligands , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Optical Rotation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The rate of change of all aspects of the life of mankind on this planet is accelerating at an ever-increasing pace. It is stated that this upheaval is directly attributable to technological changes and their interaction with social, economic and political changes. The hypothesis is advanced that this dramatically increasing rate of change is due to four unique innovations, all dealing with communications. The four are the spoken language, the written language, the printing press and the electronic computer. The accelerating rate of technological change is measured by the rate at which one hundred "technological breakthroughs" have appeared. In prehistoric times, such breakthroughs occurred tens or hundreds of thousands of years apart. Today, several appear each decade. Hope is expressed that this rapidly accelerating rate of change will enable mankind to cope with the major problems of our modern civilization. The problems specifically flagged out are population growth, human genetics, energy and pollution.