Preparation and Optimization of a Series of 3-Carboxamido-5-phenacylaminopyrazole Bradykinin B1 Receptor Antagonists

Dressen, Darren; Garofalo, Albert W.; Hawkinson, Jon E.; Hom, Dennis; Jagodziński, Jacek; Marugg, Jennifer L.; Neitzel, Martin L.; Pleiss, Michael A.; Szőke, Balázs; Tung, Jay S.; Wone, David W.G.; Wu, Jing; Zhang, Heather

doi:10.1021/jm051292n

Cited by 33 publications

(12 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Glucuronidation can also occur in intestinal microsomes, which could also to contribute to decreased bioavailability [31]. Direct N-glucuronidation to pyrazole groups of small molecule drugs has been observed previously [32–35], and has prompted the synthesis of modified analogues designed to decrease susceptibility to this metabolism [35]. The addition of electronegative groups to metabolically active heterocycles such as pyrazoles may decrease glucuronidation [36].…”

Section: Discussionmentioning

confidence: 99%

Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation

Kiesel

Parise

Guo

et al. 2016

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

Purpose The oncogenic transcription factor STAT3 promotes gene transcription involved in cancer and its activation by IL-6 is found in head and neck squamous cell carcinoma. Four triazolothiadizine STAT3 pathway inhibitors were evaluated to prioritize a single compound for in vivo examination. Methods Metabolic stability in mouse liver microsome incubation was used to evaluate four triazolothiadizine analogues, and UPCDC-10205 was administered to mice IV as single or multiple doses to evaluate toxicity. Single dose pharmacokinetics (PK), bioavailability and metabolism were studied after IV 4 mg/kg, PO 4 mg/kg, or PO 30 mg/kg suspension in 1% carboxymethyl cellulose. Mice were euthanized between 5 min to 24 h after dosing and plasma and tissues were analyzed by LC-MS. Non-compartmental PK parameters were determined. Results Of the four triazolothiadizine analogues evaluated, UPCDC-10205 was metabolically most stable. The maximum soluble dose of 4 mg/kg in 10% Solutol™ was not toxic to mice after single and multiple doses. PK analysis showed extensive tissue distribution and rapid plasma clearance. Bioavailability was ~5%. A direct glucuronide conjugate was identified as the major metabolite which was recapitulated in vitro. Conclusions Rapid clearance of UPCDC-10205 was thought to be the result of phase II metabolism despite its favorable stability in a phase I in vitro metabolic stability assay. The direct glucuronidation explains why microsomal stability (reflective of phase I metabolism) did not translate to in vivo metabolic stability. UPCDC-10205 did not demonstrate appropriate exposure to support efficacy studies in the current formulation.

show abstract

Section: Discussionmentioning

confidence: 99%

Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation

Kiesel

Parise

Guo

et al. 2016

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

show abstract

“…359,378 Upregulated in certain inflammatory states. 362 Activation associated with pain [385][386][387][388] and inflammation, 361 hyperalgesia, [382][383][384] diabetes and diabetic complications. 389 des-Arg 9 -bradykinin 423,430 associated with anxiety and depression, 415,431,432 experience of pain, 433,434 alcohol dependence, 435,436 bone formation, 437,438 angina pectoris, 439 and cardiac stability.…”

Section: Agonistmentioning

confidence: 99%

“…381 Activation of the B 1 receptor renders an increase in the cytosolic calcium ion concentration, eventually resulting in chronic and acute inflammatory responses. Notably, the B 1 receptor that is synthesized de novo in response to tissue injury is associated with hyperalgesia [382][383][384] and selective and effective drug-like antagonists to this inducible receptor may have a potential in future treatment of chronic inflammation, pain, [385][386][387][388] diabetes, and diabetic complications. 389 The arylsulfonamide 42 is one example of a potent selective B 1 antagonist discovered after extensive structure activity work starting from a nonselective series of compounds, Fig.…”

Section: Drug-like Bradykinin Receptor Antagonists and Agonistsmentioning

confidence: 99%

Neuropeptides: Metabolism to Bioactive Fragments and the Pharmacology of Their Receptors

Hallberg

2014

Medicinal Research Reviews

View full text Add to dashboard Cite

The proteolytic processing of neuropeptides has an important regulatory function and the peptide fragments resulting from the enzymatic degradation often exert essential physiological roles. The proteolytic processing generates, not only biologically inactive fragments, but also bioactive fragments that modulate or even counteract the response of their parent peptides. Frequently, these peptide fragments interact with receptors that are not recognized by the parent peptides. This review discusses tachykinins, opioid peptides, angiotensins, bradykinins, and neuropeptide Y that are present in the central nervous system and their processing to bioactive degradation products. These well-known neuropeptide systems have been selected since they provide illustrative examples that proteolytic degradation of parent peptides can lead to bioactive metabolites with different biological activities as compared to their parent peptides. For example, substance P, dynorphin A, angiotensin I and II, bradykinin, and neuropeptide Y are all degraded to bioactive fragments with pharmacological profiles that differ considerably from those of the parent peptides. The review discusses a selection of the large number of drug-like molecules that act as agonists or antagonists at receptors of neuropeptides. It focuses in particular on the efforts to identify selective drug-like agonists and antagonists mimicking the effects of the endogenous peptide fragments formed. As exemplified in this review, many common neuropeptides are degraded to a variety of smaller fragments but many of the fragments generated have not yet been examined in detail with regard to their potential biological activities. Since these bioactive fragments contain a small number of amino acid residues, they provide an ideal starting point for the development of drug-like substances with ability to mimic the effects of the degradation products. Thus, these substances could provide a rich source of new pharmaceuticals. However, as discussed herein relatively few examples have so far been disclosed of successful attempts to create bioavailable, drug-like agonists or antagonists, starting from the structure of endogenous peptide fragments and applying procedures relying on stepwise manipulations and simplifications of the peptide structures.

show abstract

“…Besides providing great biological properties, the nitrogen atoms are able to act as donors and find applications in the construction of supramolecular blocks. In this context, Pyrazole derivatives are of particular interest because of their pharmacological profile [8][9][10] such as cyclooxygenase 2 inhibitors (e.g., celecoxib, SC-558, and tepoxalin) (e.g., Fig 1) [11,12] and reduction in obesity for example cannabinoid-1 inverse agonists (e.g., rimonabant) [13].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, characterization, antimicrobial activity and molecular docking studies of combined pyrazol-barbituric acid pharmacophores

Barakat¹,

Al-Qahtani²,

Al‐Majid³

et al. 2016

Trop. J. Pharm Res

View full text Add to dashboard Cite

Preparation and Optimization of a Series of 3-Carboxamido-5-phenacylaminopyrazole Bradykinin B1 Receptor Antagonists

Cited by 33 publications

References 13 publications

Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation

Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation

Neuropeptides: Metabolism to Bioactive Fragments and the Pharmacology of Their Receptors

Synthesis, characterization, antimicrobial activity and molecular docking studies of combined pyrazol-barbituric acid pharmacophores

Contact Info

Product

Resources

About