ABSTRACT
A chromatography-free asymmetric synthesis of GDC-6036 (1) was achieved via a highly atroposelective Negishi coupling of aminopyridine 5 and quinazoline 6b catalyzed by 0.5 mol % [Pd(cin)Cl]2 and 1 mol % (R,R)-Chiraphite to afford the key intermediate (Ra)-3. An alkoxylation of (Ra)-3 with (S)-N-methylprolinol (4) and a global deprotection generates the penultimate heterobiaryl intermediate 2. A controlled acrylamide installation by stepwise acylation/sulfone elimination and final adipate salt formation and crystallization delivered high-purity GDC-6036 (1).
ABSTRACT
Oxetanes are used in drug discovery to enable physicochemical and metabolic property enhancement for the structures to which they are grafted. An imide CâO to oxetane swap on thalidomide and lenalidomide templates provides analogs with similar physicochemical and in vitro properties of the parent drugs, with an important exception: oxetane analog 2 displays a clear differentiation with respect to human plasma stability. The prospect of limiting in vivo stability/metabolism, blocking in vivo racemization, and potentially altering teratogenicity is appealing.
Subject(s)
Ethers, Cyclic/chemical synthesis , Thalidomide/analogs & derivatives , Thalidomide/chemical synthesis , Animals , Drug Discovery , Ethers, Cyclic/blood , Ethers, Cyclic/chemistry , Hepatocytes/metabolism , Humans , Lenalidomide , Mice , Microsomes, Liver/metabolism , Molecular Structure , Rats , Thalidomide/blood , Thalidomide/chemistryABSTRACT
The preparation of versatile azaspiro[3.3]heptanes carrying multiple exit vectors is disclosed. Expedient synthetic routes enable the straightforward access to these novel modules that are expected to have significance in drug discovery and design.
Subject(s)
Aza Compounds/chemical synthesis , Heptanes/chemical synthesis , Spiro Compounds/chemical synthesis , Ethers, Cyclic/chemistry , Models, Molecular , Molecular StructureABSTRACT
Sizable resources, both financial and human, are invested each year in the development of new pharmaceutical agents. However, despite improved techniques, the new compounds often encounter difficulties in satisfying and overcoming the numerous physicochemical and many pharmacological constraints and hurdles. Oxetanes have been shown to improve key properties when grafted onto molecular scaffolds. Of particular interest are oxetanes that are substituted only in the 3-position, since such units remain achiral and their introduction into a molecular scaffold does not create a new stereocenter. This Minireview gives an overview of the recent advances made in the preparation and use of 3-substituted oxetanes. It also includes a discussion of the site-dependent modifications of various physicochemical and biochemical properties that result from the incorporation of the oxetane unit in molecular architectures.
Subject(s)
Drug Design , Drug Discovery , Ethers, Cyclic/chemistry , Pharmaceutical Preparations , HumansSubject(s)
Aza Compounds/chemical synthesis , Spiro Compounds/chemical synthesis , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Aza Compounds/metabolism , Aza Compounds/pharmacology , Drug Discovery , Hepatocytes/metabolism , Humans , Molecular Structure , Spiro Compounds/metabolism , Spiro Compounds/pharmacology , Staphylococcus aureus/drug effectsABSTRACT
Straightforward access toward previously unreported substituted, heterocyclic spiro[3.3]heptanes is disclosed. These spirocyclic systems may be considered as alternatives to 1,3-heteroatom-substituted cyclohexanes, which are otherwise insufficiently stable to allow their use in drug discovery. Conformational details are discussed on the basis of X-ray crystallographic structures.
Subject(s)
Heptanes/chemical synthesis , Crystallography, X-Ray , Heptanes/chemistry , Models, Molecular , Molecular StructureABSTRACT
Trypanothione reductase (TR) is a flavoenzyme unique to trypanosomatid parasites and a target for lead discovery programs. Various inhibitor scaffolds have emerged in the past, exhibiting moderate affinity for the parasite enzyme. Herein we show that the combination of two structural motifs of known TR inhibitors - diaryl sulfides and mepacrine - enables the simultaneous addressing of two hydrophobic patches in the active site. The binding efficacy of these conjugates is enhanced over that of the respective parent inhibitors. They show K(ic) values for the parasite enzyme down to 0.9+/-0.1 microm and exhibit high selectivity for TR over human glutathione reductase (GR). Despite their considerable molecular mass and in some cases permanent positive charges, in vitro studies revealed IC(50) values in the low micromolar to sub-micromolar range against Trypanosoma brucei rhodesiense and Trypanosoma cruzi, as well as the malaria parasite Plasmodium falciparum, which lack trypanothione metabolism. The inhibitors exhibit strong fluorescence due to their aminoacridine moiety. This feature allows visualization of the drugs in the parasite where high accumulation was observed by fluorescence microscopy even after short exposure times.