Pyrazole

About: Pyrazole is a research topic. Over the lifetime, 12131 publications have been published within this topic receiving 151905 citations. The topic is also known as: 1,2-Diazole & Hpz.

Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib).

Abstract: A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.

A Highly Selective Catalytic Method for the Oxidative Functionalization of C−H Bonds

Abstract: This communication describes a new and highly practical Pd(II)-catalyzed method for the regio- and chemoselective oxidative functionalization of arenes and alkanes. Carbon−hydrogen bonds of substrates that contain a variety of directing groups (e.g., pyridine, azobenzene, pyrazole, and imine derivatives) are selectively transformed into esters, ethers, and aryl-halides under mild conditions. The scope of this reaction in terms of substrate, directing group, and oxidant is described, and a preliminary catalytic cycle is proposed.

Pyrazole Ligands: Structure−Affinity/Activity Relationships and Estrogen Receptor-α-Selective Agonists

Abstract: We have found that certain tetrasubstituted pyrazoles are high-affinity ligands for the estrogen receptor (ER) (Fink et al Chem Biol 1999, 6, 205-219) and that one pyrazole is considerably more potent as an agonist on the ERalpha than on the ERbeta subtype (Sun et al Endocrinology 1999, 140, 800-804) To investigate what substituent pattern provides optimal ER binding affinity and the greatest enhancement of potency as an ERalpha-selective agonist, we prepared a number of tetrasubstituted pyrazole analogues with defined variations at certain substituent positions Analysis of their binding affinity pattern shows that a C(4)-propyl substituent is optimal and that a p-hydroxyl group on the N(1)-phenyl group also enhances affinity and selectivity for ERalpha The best compound in this series, a propylpyrazole triol (PPT, compound 4g), binds to ERalpha with high affinity (ca 50% that of estradiol), and it has a 410-fold binding affinity preference for ERalpha It also activates gene transcription only through ERalpha Thus, this compound represents the first ERalpha-specific agonist We investigated the molecular basis for the exceptional ERalpha binding affinity and potency selectivity of pyrazole 4g by a further study of structure-affinity relationships in this series and by molecular modeling These investigations suggest that the pyrazole triols prefer to bind to ERalpha with their C(3)-phenol in the estradiol A-ring binding pocket and that binding selectivity results from differences in the interaction of the pyrazole core and C(4)-propyl group with portions of the receptor where ERalpha has a smaller residue than ERbeta These ER subtype-specific interactions and the ER subtype-selective ligands that can be derived from them should prove useful in defining those biological activities in estrogen target cells that can be selectively activated through ERalpha