The nonpeptide WIN 64338 is a bradykinin B2 receptor antagonist (original) (raw)

Design and Synthesis of New Linear and Cyclic Bradykinin Antagonists

Journal of Medicinal Chemistry, 1996

We report here on the synthesis and pharmacological properties of a new series of small linear and cyclic peptides derived from the five C-terminal amino acid residues of second-generation bradykinin receptor antagonists. Variations of the two first residues of the pentapeptide (Thi-Ser-D-Tic-Oic-Arg) were shown to modulate the biological activities of the analogs on bradykinininduced smooth muscle contractions in rabbit jugular vein (RJV), a tissue preparation specific of the B2 bradykinin receptor. Several analogs showed pA 2 values around 7 on this tissue preparation, and one cyclic compound, c[-Gly-Thi-D-Tic-Oic-Arg-], 24, in which Thi-Ser was replaced by Gly-Thi, displayed a pA 2 of 7.4 on RJV. On the basis of these results, three cyclic molecules and their linear counterparts (compounds 22-24 and 4-6, respectively) were tested on human umbilical vein, a tissue specific of the human B2 receptor. The pK B values obtained for these compounds on these tissue preparations were equivalent to those obtained for the decapeptide NPC 567 (4.8 < pA 2 < 5.1). NMR and molecular modeling studies performed on compound 24 clearly demonstrated a type II′-turn structure. This analog may serve as a new lead for the design of nonpeptide ligands of the bradykinin B2 receptor subtype.

Novel Subtype-Selective Nonpeptide Bradykinin Receptor Antagonists FR167344 and FR173657

Molecular Pharmacology, 1997

We describe the receptor binding and antagonistic properties of two novel nonpeptide antagonists, FR167344 (3-bromo-8-[2,6dichloro-3-[N-[(E)-4-(N,N-dimethylcarbamoyl)cinnamidoacetyl]-Nmethylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine hydrochloride) and FR173657 (8-[3-[N-[(E)-3-(6-acetamidopyridin-3yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2methylquinoline), for the human bradykinin receptor subtypes (B 1 and B 2). In competitive experiments using membranes prepared from Chinese hamster ovary cells expressing the bradykinin receptor subtypes, FR167344 and FR173657 showed a high affinity binding to the B 2 receptor with IC 50 values of 65 and 8.9 nM, respectively, and no binding affinity for the B 1 receptor. FR167344 and FR173657 inhibited the B 2 receptor-mediated phosphatidylinositol (PI) hydrolysis and produced a concentration-dependent rightward shift in the dose-response curve to bradykinin. This shift was accompanied by a progressive reduction of maximal response. Estimated pA 2 values for the antagonism of bradykinininduced PI hydrolysis by FR167344 and FR173657 were 8.0 and 9.0, respectively. FR167344 and FR173657 showed no stimulatory effects on PI hydrolysis. Therefore, FR167344 and FR173657 are potent, highly selective, and insurmountable antagonists for the human bradykinin B 2 receptor.

New agonist and antagonist analogues of bradykinin

Canadian Journal of Physiology and Pharmacology, 1984

Three new analogues of bradykinin (BK) have been tested for their agonistic and antagonistic actions on the rabbit jugular vein and the guinea pig ileum (B2 receptors), and six were studied on rabbit aorta strips (B1 receptors). Substitution of Gly4, Phe5, and Phe8 in BK with D-Trp gives analogues with a relative affinity lower than 1.0% as compared with BK. These analogues have no antagonistic properties on the rabbit jugular vein and on guinea pig ileum (B2 receptors). Substitution of Pro7 in des-Arg9-BK by Gly and by D-Ala give compounds that antagonise the effects of kinins on the rabbit aorta strips (B1-receptor system). These new antagonists are fairly potent with a pA2 value of 6.03 to 7.29 and seem competitive because the pA2 – pA10 values approximate 0.95. These results suggest that the orientation of Phe8 is critical for the activation of B1 receptors by kinins.

Bradykinin analogues: differential agonist and antagonist activities suggesting multiple receptors

British Journal of Pharmacology, 1988

Bradykinin analogues with specific antagonist activity in several bioassays were evaluated for effects on [3H]‐bradykinin receptor binding sites and inositol phosphate production in neuroblastoma N1E‐115 cells. The analogues varied in their affinities for bradykinin receptors in guinea‐pig ileum and N1E‐115 cell membranes, in their effects on uterine and ileal contractions and in their agonist or antagonist activity on phosphoinositide turnover in N1E‐115 cells. These tissue specific effects suggest the presence of multiple bradykinin receptor subtypes.

Novel small molecule bradykinin B1 receptor antagonists. Part 1: Benzamides and semicarbazides

Bioorganic & Medicinal Chemistry Letters, 2010

The synthesis and SAR of two series of bradykinin B 1 receptor antagonists is described. The benzamide moiety proved to be a suitable replacement for the aryl ester functionality of biaryl based antagonists. In addition, it was found that semicarbazides can effectively replace cyclopropyl amino acids. The compounds with the best overall profile were biaryl semicarbazides which display high antagonistic activity, low Caco-2 efflux and high oral bioavailability in the rat.

Bradykinin B1 antagonists: Biphenyl SAR studies in the cyclopropanecarboxamide series

Bioorganic & Medicinal Chemistry Letters, 2007

SAR study of the biphenyl region of cyclopropanecarboxamide derived bradykinin B 1 antagonists was examined. Incorporation of a pyridine in place of the proximal phenyl ring and chlorination of the distal phenyl ring proved to be well tolerated and provided compounds with improved pharmacokinetic profiles, CNS penetration, and enhanced receptor occupancy.

In Vitro Pharmacological Profile of a New Small Molecule Bradykinin B2 Receptor Antagonist

Frontiers in Pharmacology, 2020

We here report the discovery and early characterization of Compound 3, a representative of a novel class of small molecule bradykinin (BK) B 2 receptor antagonists, and its superior profile to the prior art B 2 receptor antagonists Compound 1 and Compound 2. Compound 3, Compound 2, and Compound 1 are highly potent antagonists of the human recombinant B 2 receptor (K b values 0.24, 0.95, and 1.24 nM, respectively, calcium mobilization assay). Compound 3 is more potent than the prior art compounds and icatibant in this assay (K b icatibant 2.81 nM). The compounds also potently inhibit BK-induced contraction of endogenous B 2 receptors in a human isolated umbilical vein bioassay. The potencies of Compound 3, Compound 2, Compound 1, and icatibant are (pA 2 values) 9.67, 9.02, 8.58, and 8.06 (i.e. 0.21, 0.95, 2.63, and 8.71 nM), respectively. Compound 3 and Compound 2 were further characterized. They inhibit BK-induced c-Fos signaling and internalization of recombinant human B 2 receptors in HEK293 cells, and do not antagonize the venous effects mediated by other G protein-coupled receptors in the umbilical vein model, including the bradykinin B 1 receptor. Antagonist potency of Compound 3 at cloned cynomolgus monkey, dog, rat, and mouse B 2 receptors revealed species selectivity, with a high antagonist potency for human and monkey B 2 receptors, but several hundred-fold lower potency for the other B 2 receptors. The in vitro off-target profile of Compound 3 demonstrates a high degree of selectivity over a wide range of molecular targets, including the bradykinin B 1 receptor. Compound 3 showed a lower intrinsic clearance in the microsomal stability assay than the prior art compounds. With an efflux ratio of 1.0 in the Caco-2 permeability assay Compound 3 is predicted to be not a substrate of efflux pumps. In conclusion, we discovered a novel chemical class of highly selective and very potent B 2 receptor antagonists, as exemplified by Compound 3. The compound showed excellent absorption in the Caco-2 assay, predictive of good oral bioavailability, and favourable metabolic stability in liver microsomes. Compound 3 has provided a significant stepping stone towards the discovery of the orally bioavailable B 2 antagonist PHA-022121, currently in phase 1 clinical development.

Effect of bradykinin analogues on the B1 receptor of rat ileum

Peptides, 2003

The longitudinal muscle of isolated rat ileum is a sensitive bioassay suitable for testing compounds with antagonistic effects on the B 1 receptor. Bradykinin analogues with replacement of proline by alkyl-substituted phenylalanine at position 7 are effective on this receptor as entire molecules and have a stronger antagonistic effect than on the B 2 receptor. A corresponding desArg 9-compound has a specific effect on the B 1 receptor and a very high antagonistic potency. [LNMPhe 2 ]bradykinin as a compound without any replacement at position 7 or 8 shows antagonistic activity as well.