215 research outputs found
Cyclooxygenase-2 inhibitors. 1,5-diarylpyrrol-3-acetic esters with enhanced inhibitory activity toward cyclooxygenase-2 and improved cyclooxygenase-2/cyclooxygenase-1 selectivity.
he important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effect limitations of current COX-2 inhibitor drugs illustrates a need for the design of new compounds based on alternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selective COX-2 inhibitors and their affinity data were rationalized through docking simulations. In this paper, we describe the synthesis of new 1,5-diarylpyrrole derivatives that were assayed for their in vitro inhibitory effects toward COX isozymes. Among them, the ethyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-fluorophenyl]-1H-pyrrol-3- acetate (1d), which was the most potent and COX-2 selective compound, also showed a very interesting in vivo anti-inflammatory and analgesic activity, laying the foundations for developing new lead compounds that could be effective agents in the armamentarium for the management of inflammation and pain
Weak formulation for singular diffusion equation with dynamic boundary condition
In this paper, we propose a weak formulation of the singular diffusion
equation subject to the dynamic boundary condition. The weak formulation is
based on a reformulation method by an evolution equation including the
subdifferential of a governing convex energy. Under suitable assumptions, the
principal results of this study are stated in forms of Main Theorems A and B,
which are respectively to verify: the adequacy of the weak formulation; the
common property between the weak solutions and those in regular problems of
standard PDEs.Comment: 23 page
The prescribed mean curvature equation in weakly regular domains
We show that the characterization of existence and uniqueness up to vertical
translations of solutions to the prescribed mean curvature equation, originally
proved by Giusti in the smooth case, holds true for domains satisfying very
mild regularity assumptions. Our results apply in particular to the
non-parametric solutions of the capillary problem for perfectly wetting fluids
in zero gravity. Among the essential tools used in the proofs, we mention a
\textit{generalized Gauss-Green theorem} based on the construction of the weak
normal trace of a vector field with bounded divergence, in the spirit of
classical results due to Anzellotti, and a \textit{weak Young's law} for
-minimizers of the perimeter.Comment: 23 pages, 1 figure --- The results on the weak normal trace of vector
fields have been now extended and moved in a self-contained paper available
at: arXiv:1708.0139
Novel ester and acid derivatives of the 1,5-diarylpyrrole scaffold as anti-inflammatory and analgesic agents. Synthesis and in vitro and in vivo biological evaluation.
A new generation of selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) was developed to circumvent the major side effects of cyclooxygenase-1 (COX-1) and COX-2 inhibitors (stomach ulceration and nephrotoxicity). As a consequence, coxibs are extremely valuable in treating acute and chronic inflammatory conditions. However, the use of coxibs, such as rofecoxib (Vioxx), was discontinued because of the high risk of cardiovascular adverse events. More recent clinical findings highlighted how the cardiovascular toxicity of coxibs could be mitigated by an appropriate COX-1 versus COX-2 selectivity. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, selective for COX-2. Here, we describe the synthesis of new 1,5-diarylpyrroles along with their inhibitory effects in vitro, ex vivo, and in vivo toward COX isoenzymes and their analgesic activity. Isopropyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-phenyl-1H-pyrrole-3-acetate (10a), a representative member of the series, was selected for pharmacokinetic and metabolic studies
Novel ester and acid derivatives of the 1,5-diarylpyrrole scaffold as anti-inflammatory and analgesic agents. Synthesis and in vitro and in vivo biological evaluation.
A new generation of selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) was developed to circumvent the major side effects of cyclooxygenase-1 (COX-1) and COX-2 inhibitors (stomach ulceration and nephrotoxicity). As a consequence, coxibs are extremely valuable in treating acute and chronic inflammatory conditions. However, the use of coxibs, such as rofecoxib (Vioxx), was discontinued because of the high risk of cardiovascular adverse events. More recent clinical findings highlighted how the cardiovascular toxicity of coxibs could be mitigated by an appropriate COX-1 versus COX-2 selectivity. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, selective for COX-2. Here, we describe the synthesis of new1,5-diarylpyrroles along with their inhibitory effects in vitro, ex vivo, and in vivo toward COX isoenzymes and their analgesic activity. Isopropyl-2-methyl-5-[4- (methylsulfonyl)phenyl]-1-phenyl-1H-pyrrole-3-acetate (10a), a representative member of the series, was selected for pharmacokinetic and metabolic studies
Novel analgesic/anti-inflammatory agents: 1,5-diarylpyrrole nitrooxyalkyl ethers and related compounds as cyclooxygenase-2 inhibiting nitric oxide donors
A series of 3-substituted 1,5-diarylpyrroles bearing a nitrooxyalkyl side chain linked to different spacers were designed. New classes of pyrrole-derived nitrooxyalkyl inverse esters, carbonates, and ethers (7-10) as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitrooxyalkyl ethers (9, 10) into corresponding alcohols, derivatives 17 and 18 were also studied. Nitrooxy derivatives showed NO-dependent vasorelaxing properties, while most of the compounds proved to be very potent and selective COX-2 inhibitors in in vitro experimental models. Further in vivo studies on compounds 9a,c and 17a highlighted good anti-inflammatory and antinociceptive activities. Compound 9c was able to inhibit glycosaminoglycan (GAG) release induced by interleukin-1β (IL-1β), showing cartilage protective properties. Finally, molecular modeling and (1)H- and (13)C-NMR studies performed on compounds 6c,d, 9c, and 10b allowed the right conformation of nitrooxyalkyl ester and ether side chain of these molecules within the COX-2 active site to be assessed
Existence, regularity and boundary behaviour of bounded variation solutions of a one-dimensional capillarity equation
n/
Existence of Integral -Varifolds minimizing and , , in Riemannian Manifolds
We prove existence and partial regularity of integral rectifiable
-dimensional varifolds minimizing functionals of the type and
in a given Riemannian -dimensional manifold , , under suitable assumptions on (in the end of the paper we
give many examples of such ambient manifolds). To this aim we introduce the
following new tools: some monotonicity formulas for varifolds in
involving , to avoid degeneracy of the minimizer, and a sort of
isoperimetric inequality to bound the mass in terms of the mentioned
functionals.Comment: 33 pages; this second submission corresponds to the published version
of the paper, minor typos are fixe
Multidimensional Conservation Laws: Overview, Problems, and Perspective
Some of recent important developments are overviewed, several longstanding
open problems are discussed, and a perspective is presented for the
mathematical theory of multidimensional conservation laws. Some basic features
and phenomena of multidimensional hyperbolic conservation laws are revealed,
and some samples of multidimensional systems/models and related important
problems are presented and analyzed with emphasis on the prototypes that have
been solved or may be expected to be solved rigorously at least for some cases.
In particular, multidimensional steady supersonic problems and transonic
problems, shock reflection-diffraction problems, and related effective
nonlinear approaches are analyzed. A theory of divergence-measure vector fields
and related analytical frameworks for the analysis of entropy solutions are
discussed.Comment: 43 pages, 3 figure
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