ABSTRACT
A series of TRPA1 antagonists is described having a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine or a 1-aryloxyisoquinoline scaffold. These compounds have high ligand efficiency and favorable physical properties and may thus serve as scaffolds for further optimization.
Subject(s)
Drug Discovery , Isoquinolines/pharmacology , Nerve Tissue Proteins/antagonists & inhibitors , Pyridines/pharmacology , Pyrroles/pharmacology , Transient Receptor Potential Channels/antagonists & inhibitors , Calcium Channels , Dose-Response Relationship, Drug , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity Relationship , TRPA1 Cation ChannelABSTRACT
Generalized models of joint surface shapes are the foundation for mechanism studies on the mechanical effects of rock joint surface shapes. Based on extensive field investigations of rock joint surface shapes, generalized models for three level shapes named macroscopic outline, surface undulating shape, and microcosmic roughness were established through statistical analyses of 20,078 rock joint surface profiles. The relative amplitude of profile curves was used as a borderline for the division of different level shapes. The study results show that the macroscopic outline has three basic features such as planar, arc-shaped, and stepped; the surface undulating shape has three basic features such as planar, undulating, and stepped; and the microcosmic roughness has two basic features such as smooth and rough.
Subject(s)
Models, TheoreticalABSTRACT
Purinergic receptor P2X3 has been linked to analgesia in a number of pre-clinical models of pain, and is expressed in the human pain perception pathway. Only few P2X3-selective antagonists have been reported to date. This Letter describes the SAR and in vivo analgesic profile of a novel scaffold of selective P2X3 antagonists.
Subject(s)
Analgesics/chemical synthesis , Chronic Pain/drug therapy , Purinergic P2 Receptor Antagonists/chemical synthesis , Pyrimidinones/chemical synthesis , Pyrroles/chemical synthesis , Receptors, Purinergic P2X3/chemistry , Analgesics/administration & dosage , Analgesics/therapeutic use , Animals , Chronic Pain/metabolism , Dose-Response Relationship, Drug , High-Throughput Screening Assays , Humans , Injections, Spinal , Injections, Subcutaneous , Purinergic P2 Receptor Antagonists/administration & dosage , Purinergic P2 Receptor Antagonists/therapeutic use , Pyrimidinones/administration & dosage , Pyrimidinones/therapeutic use , Pyrroles/administration & dosage , Pyrroles/therapeutic use , Rats , Rats, Sprague-Dawley , Receptors, Purinergic P2X3/metabolism , Small Molecule LibrariesABSTRACT
A series of novel N-alkyl linkers that connect small-molecule library members with their encoding DNA oligonucleotides has been developed. In comparison with the standard amide linker (usually constructed with oligo-AOP-NH2 ), the N-alkyl linker is not only more chemically stable, but also provides better structural diversity at the linkage point. Chemical variety in the vicinity of the polyglycol terminus, in particular, could affect binding interactions with the target protein. It could have been neglected in previous DNA-encoded chemical library (DEL) synthesis and screening studies due to the limited linkage alternatives. With these linkers, one can produce versatile key intermediates as Cycleâ 1 products directly amenable to Cycleâ 2 chemistry without the use of protecting groups. As a result, a DEL synthesis process that uses the fewest chemical conversions, such as 3-step, 3-cycle DELs, can achieve higher synthetic efficiency while creating less DNA tag degradation, resulting in higher quality DELs.
Subject(s)
Drug Discovery , Small Molecule Libraries , DNA/chemistry , Drug Discovery/methods , Gene Library , Small Molecule Libraries/chemistryABSTRACT
Geopolymer is a new type of synthesized aluminosilicate material. Compared with ordinary Portland cement, it has better fire resistance and durability, and is more environmentally friendly. In this paper, a high-strength metakaolin-based geopolymer composite (HMGC) has been developed by utilizing quartz powder and steel fibers. The optimization compositions and effect of curing temperatures (from ambient temperature to 90 °C) on the strength performance of the HMGC is studied. The optimized 1-day compressive strength of the HMGC can reach 80 MPa, and the 3-day compressive strength is close to 100 MPa (97.49 MPa). Combined with XRD, FTIR, SEM and MIP characterization, the mechanisms behind the strength development under different curing temperatures are analyzed. The results show that heat curing can significantly speed up the process of geopolymerization and increase the early strength of the HMGC. However, long-term heat curing under high temperature (such as 90 °C, 7 days) would reduce the mechanical strength of the HMGC. Prolonged high-temperature curing increases the pores and micro-defects in the gel phase of the HMGC, which may be attributed to chemical shrinkage. Thus, the curing temperature should be carefully controlled to make a HMGC with better performance.
ABSTRACT
2,4-Diaminopyrimidines derivatives were developed as a novel class of SNSR4 antagonists. Structure activity relationship of the diamino pyrimidine core was explored and a tool compound suitable for target validation was identified.
Subject(s)
Pyrimidines/pharmacology , Receptors, Cell Surface/antagonists & inhibitors , Sensory Receptor Cells/drug effects , Inhibitory Concentration 50 , Sensory Receptor Cells/metabolismABSTRACT
A series of macrocyclic analogues were designed and synthesized based on the cocrystal structure of small molecule plasma kallikrein (pKal) inhibitor, 2, with the pKal protease domain. This led to the discovery of a potent macrocyclic pKal inhibitor 29, with an IC50 of 2 nM for one olefinic isomer and 42.3 nM for the other olefinic isomer.
ABSTRACT
This paper presents a formal total synthesis of 3-deoxy-D-manno-2-octulosonic acid (KDO) based on a highly double-stereoselective hetero Diels-Alder reaction between an electron-rich diene and ethyl glyoxylate catalyzed by (Salen)Co(II) complex, a new catalyst for Diels-Alder reactions. A facial specific hydroboration followed by oxidative workup leads to a diol system with the trans-diequatorial arrangement of hydroxyl groups at the C-4 and C-5. Inversion of the configuration of the C-5 hydroxyl group in 12 and then ketal formation afford the desired target diisopropylidene-2-deoxy-KDO methyl ester (18), which can be converted to KDO according to the literature procedure.