Cyclopropylamino Acid Amide as a Pharmacophoric Replacement for 2,3-Diaminopyridine. Application to the Design of Novel Bradykinin B₁ Receptor Antagonists

Abstract

Antagonism of the bradykinin B1 receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists were designed that display low-nanomolar affinity for the human bradykinin B1 receptor and good bioavailability in the rat.

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

“…(Figure 49) It was reasoned that the favorable PK profile of compound 118 could be a combined effect of the stability of unnatural α-amino acids towards proteolytic enzymes, in concert with the absence of the metabolically reactive diaminopyridine scaffold. 153 Although compound 118 had reasonable affinity towards B1 receptor, it did not have optimal PK Page 40 of 138 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 properties and had only moderate CNS receptor occupancy. Moreover, compound 118-related structures were found to be substrates of P-gp, thereby compromising their CNS penetration.…”

N‐(Anilinoethyl)amides: Design and Synthesis of Metabolically Stable, Selective Melatonin Receptor Ligands

“…Although the cyclopropylcarbonyl can occupy the same space as the phenyl ring, it demonstrated resistance to metabolic transformation in a different series of pharmacologically active compounds. [35] The methoxy was replaced with either trifluoromethoxy (4 e) or bromine (4 f) moieties. Bromine had been reported as a bioisostere for the methoxy group in the N-(anilinoethyl)amido ligand series, enabling satisfactory conservation of binding affinity, MT 2 selectivity, and intrinsic activity.…”

The Influence of Bioisosteres in Drug Design: Tactical Applications to Address Developability Problems

“…The potent bradykinin B 1 antagonist 266 , K i = 11.8 nM, developed as a potential treatment for pain, was found to produce glutathione adducts when incubated in rat and human liver microsomal preparations, a metabolic pathway also observed in vivo following oral administration of the drug to rats with GSH adducts derived from the drug identified in bile [ 372 ]. The site of GSH adduction was determined to be the pyridine ring, characterized as 268 and hypothesized to arise either from the diiminoquinone 267 or the epoxide 270 , while the pyridine N-oxide 269 was determined to be a minor contributory pathway.…”