Edward Karol Dziadulewicz

Bradyzide, a potent non-peptide B2 bradykinin receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesia

Bradyzide is from a novel class of rodent‐selective non‐peptide B2 bradykinin antagonists (1‐(2‐Nitrophenyl)thiosemicarbazides). Bradyzide has high affinity for the rodent B2 receptor, displacing [3H]‐bradykinin binding in NG108‐15 cells and in Cos‐7 cells expressing the rat receptor with KI values of 0.51±0.18 nM (n=3) and 0.89±0.27 nM (n=3), respectively. Bradyzide is a competitive antagonist, inhibiting B2 receptor‐induced 45Ca efflux from NG108‐15 cells with a pKB of 8.0±0.16 (n=5) and a Schild slope of 1.05. In the rat spinal cord and tail preparation, bradyzide inhibits bradykinin‐induced ventral root depolarizations (IC50 value; 1.6±0.05 nM (n=3)). Bradyzide is much less potent at the human than at the rodent B2 receptor, displacing [3H]‐bradykinin binding in human fibroblasts and in Cos‐7 cells expressing the human B2 receptor with KI values of 393±90 nM (n=3) and 772±144 nM (n=3), respectively. Bradyzide inhibits bradykinin‐induced [3H]‐inositol trisphosphate (IP3) formation with IC50 values of 11.6±1.4 nM (n=3) at the rat and 2.4±0.3 μM (n=3) at the human receptor. Bradyzide does not interact with a range of other receptors, including human and rat B1 bradykinin receptors. Bradyzide is orally available and blocks bradykinin‐induced hypotension and plasma extravasation. Bradyzide shows long‐lasting oral activity in rodent models of inflammatory hyperalgesia, reversing Freunds complete adjuvant (FCA)‐induced mechanical hyperalgesia in the rat knee joint (ED50, 0.84 μmol kg−1; duration of action >4 h). It is equipotent with morphine and diclofenac, and 1000 times more potent than paracetamol, its maximal effect exceeding that of the non‐steroidal anti‐inflammatory drugs (NSAIDs). Bradyzide does not exhibit tolerance when administered over 6 days. In summary, bradyzide is a potent, orally active, antagonist of the B2 bradykinin receptor, with selectivity for the rodent over the human receptor.

The design of non-peptide human bradykinin B2 receptor antagonists employing the benzodiazepine peptidomimetic scaffold

The Bradykinin B2 receptor antagonist HOE 140 (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg) has been used as a template for the de novo design and synthesis of a small number of non-peptide lead compounds based on the 1,4-benzodiazepin-2-one framework. Two of the compounds have been found to exhibit moderate K(i) values of 8.9 and 9.2 microM at the human Bradykinin B2 receptor.

Drug profile: transdermal rivastigmine patch in the treatment of Alzheimer disease.

Cholinesterase inhibitors constitute one of the mainstays of treatment of Alzheimer disease (AD). Gastrointestinal side effects, difficulty accessing therapeutic doses and poor patient compliance have been identified as barriers to effective treatment with these substances. The rivastigmine transdermal patch provides continuous delivery of drug through the skin into the bloodstream, avoiding the fluctuations in plasma concentration associated with oral administration. This pharmacokinetic profile is associated with reduced side effects, resulting in easier access to expected target doses. These benefits, along with other practical advantages of the transdermal patch, may contribute to enhanced patient compliance. Here, we present a review of the current literature on rivastigmine patch, and offer advice based on our own collective clinical experience. Rivastigmine patch provides an efficient option for managing patients with AD, to be considered among the first line therapies for the disease.

CONCISE AND REGIOSPECIFIC SYNTHESES OF TRI-SUBSTITUTED 1,2,4-TRIAZOLES

Abstract Novel tri-substituted 1,2,4-triazoles are synthesized via complementary, regiospecific routes as part of a lead finding exercise. A key feature of one of the syntheses is recognition of an intrinsic regioselectivity toward deprotonation in the 1-phenylguanazole substrate.

Non-peptide ligands for bradykinin receptors 1995 – 2004

It has been a decade since the area of bradykinin (BK) research was last reviewed in this journal. Within this period of time, selective, high-affinity non-peptide BK ligands have been identified by different research groups for both the B1 and B2 receptors (B1R and B2R). The efficacies of these agents in animal models of human diseases suggest that it may be possible to develop such compounds into novel classes of therapeutic drugs. The emerging pharmacological evidence from these studies suggests that B1R and B2R antagonists may be clinically useful for the treatment of pain, inflammation, cancer, hypotension, asthma, colitis, rhinitis, pancreatitis, sepsis and rheumatoid arthritis. B2R agonists, on the other hand, may alleviate cardiovascular disorders, such as congestive heart failure, hypertension and ischaemic heart disease, and are potentially useful for the treatment of diabetic disorders by mimicking the beneficial effects of BK on glucose uptake and insulin sensitivity. A major challenge in targeting the B2R is maintaining a balance between the opposing beneficial (cardioprotective, anti-inflammatory) and debilitating (pro-inflammatory, cardiocompromising) effects upon activation or inhibition of this receptor subtype. For this reason, the last few years have seen a significant shift in research emphasis to the B1R subtype due to its disease-dependent expression. This review will focus on the advances in BK medicinal chemistry reported between 1995 and the beginning of December 2004, with particular emphasis on small-molecule patent disclosures made during this period.

A non-peptide antagonist unusually selective for the human form of the bradykinin B2 receptor

Analgesic and anti-inflammatory applications for non-peptide bradykinin (BK) B2 receptor antagonists have been documented in rats. However, very large species differences in affinity were also noted within this class of drugs, making the preclinical development of relevant drugs difficult. Bradyzide is a potent antagonist at the rat B2 receptor, but a weak one at the human receptor; a series of analogues in which the diphenylmethyl moiety of this drug has been substituted with dibenzosuberane have been reported to gain potency at the human B2 receptor, with some loss of affinity at the rat receptor. The present experiments have been performed in order to verify that the novel series of dibenzosuberane B2 receptor antagonist optimized for affinity in the human species are effective in the isolated human umbilical vein contractility assay. Bradyzide, its analog compound (S)-14c and the dibenzosuberane compounds (S)-14d and 19c surmountably antagonized BK-induced contraction (pA2 values of 5.42, 6.48, 7.42 and 7.53, respectively). In the rabbit jugular vein contractility assay, the pA2 of compound 19c was smaller than 5. Potency at the recombinant rabbit B2 receptor was generally decreasing in the series of four drugs (Ki in a [3H]BK competition assay to recombinant receptors of 0.78, 0.77, 10.2 and 44.4 nM, respectively); these four compounds did not displace [3H]Lys-des-Arg(9)-BK binding from human B1 receptors expressed by smooth muscle cells. The dibenzosuberane compound 19c, verified to functionally antagonize the vascular B2 receptor, is an example of a drug unusually specific for the human form of the receptor.

Effects of two novel non-peptide antagonists at the rabbit bradykinin B2 receptor

Large species differences have been previously observed in the pharmacology of bradykinin (BK) B2 receptor antagonists. We investigated the effect of two novel non-peptide antagonists, compound 9 (a benzodiazepine peptidomimetic related to icatibant) and the thiosemicarbazide bradyzide on the rabbit B2 receptor (contractility of the jugular vein, competition of [3H]BK binding to a B2 receptor-green fluorescent protein (B2R-GFP) conjugate, subcellular distribution of B2R-GFP). While compound 9 is about 9000-fold less potent than icatibant, it shares with the latter peptide drug a selective, insurmountable and largely irreversible antagonist behavior against BK and the capacity to translocate B2R-GFP from the membrane into the cells. Bradyzide, reportedly very potent at rodent B2 receptors, was a competitive and reversible antagonist of moderate potency at the rabbit B2 receptor (contractility pA2 6.84, binding competition IC50 5 nM). The C-terminal region of icatibant, reproduced by compound 9, is likely to be important in the non-equilibrium behavior of icatibant. Bradyzide, a non-peptide antagonist developed on different structural grounds, is competitive at the rabbit B2 receptor.

Design of non-peptide CCK2 and NK1 peptidomimetics using 1-(2-nitrophenyl)thiosemicarbazide as a novel common scaffold

A beta-turn overlay hypothesis has been used to transform the core scaffold of a selective non-peptide bradykinin B2 receptor antagonist into ligands specifically recognized by the CCK2 or NK1 receptors.

Bradykinin B2 Receptor Antagonists for the Treatment of Pain

Publisher Summary The bradykinin B2 receptor is a mature G-protein coupled receptor target that has long offered the prospect of therapeutic intervention in pain and inflammation, but this has been notoriously difficult to achieve. This chapter discusses the kinin B2 receptor as a therapeutic target, peptide bradykinin B2 receptor antagonists, and non-peptide bradykinin B2 receptor antagonists. The cloned human B2 receptor is composed of 364 amino acids and is phylogenetically only 36% identical to the human B1 receptor. In contrast to the B1 subtype, B2 receptors are expressed constitutively in most cell and tissue types and mediate most of the known effects of BK and KD when these are produced in plasma and tissues, respectively. There is evidence that activation of B2 receptors engages multiple signal transduction pathways, leading to production of pro-inflammatory cytokines, such as interleukin-1β, and induction of the transcriptional nuclear factor-κB. These entities are subsequently capable of inducing the upregulation and expression of B1 receptors, potentiating the inflammatory response further. Potent, selective and orally active non-peptide B2 receptor antagonists have emerged as potential therapeutic agents and have demonstrated efficacy in various animal models of inflammatory pain. However, although most patent applications cite pain as a major indication, no B2 antagonist has been successfully shepherded through clinical trials to registration, despite a substantial industry-wide preclinical effort.