Design and Synthesis of Novel Sulfonamide-Containing Bradykinin hB₂ Receptor Antagonists. 2. Synthesis and Structure−Activity Relationships of α,α-Cycloalkylglycine Sulfonamides

Abstract

Recently we reported on the design and synthesis of a novel class of selective nonpeptide bradykinin (BK) B2 receptor antagonists (J. Med. Chem. 2006, 3602-3613). This work led to the discovery of MEN 15442, an antagonist with subnanomolar affinity for the human B2 receptor (hB2R), which also displayed significant and prolonged activity in vivo (for up to 210 min) against BK-induced bronchoconstriction in the guinea-pig at a dose of 300 nmol/kg (it), while demonstrating only a slight effect on BK-induced hypotension. Here we describe the further optimization of this series of compounds aimed at maximizing the effect on bronchoconstriction and minimizing the effect on hypotension, with a view to developing topically delivered drugs for airway diseases. The work led to the discovery of MEN 16132, a compound which, after intratracheal or aerosol administration, inhibited, in a dose-dependent manner, BK-induced bronchoconstricton in the airways, while showing minimal systemic activity. This compound was selected as a preclinical candidate for the topical treatment of airway diseases involving kinin B2 receptor stimulation.

Comparison of the molecular interactions of two antagonists, MEN16132 or icatibant, at the human kinin B2 receptor

“…Using mutagenesis of the human B 2 receptor, we previously presented data on the essential role of the quinoline moiety of non‐peptide antagonists and its interaction with some residues belonging to TM3, TM6 and TM7 (Meini et al ., 2004), which together define a lipophilic receptor binding crevice in a part of the receptor involved in the balance of active/inactive protein conformers, either for the human B 2 receptor or other GPCRs (Gether and Kobilka, 1998; Marie et al ., 2001; Rosenbaum et al ., 2009). In this study, our efforts are focused on finding specific receptor counterparts for the other pharmacophores of MEN16132, such as the tetrahydropyranyl and the quaternary ammonium groups, which were known to be important for high affinity ligand–receptor interaction from structure–activity relationship studies (Fattori et al ., 2006; 2007). The W86 residue was identified as being involved both in the binding interaction of agonist and other non‐peptide antagonists besides MEN16132 (Meini et al ., 2002; Bellucci et al ., 2003), but not peptide antagonists such as icatibant or MEN11270 (this study; Meini et al ., 2002).…”

“…Present data obtained from the wild type receptor cell system indicate that MEN16132 displays an even higher antagonist potency also towards the B 2 receptor activation mediated by the non‐peptide agonist FR190997 (pA 2 9.1–9.6). We consider the reduction of potency and the minor insurmountable antagonist behaviour observed with MEN16132 at the D266A/D284A B 2 receptor mutant, as indicative of an interaction of these residues with the basic quaternary ammonium group, previously shown to contribute to the high antagonist potency of this compound (Fattori et al ., 2006; 2007) (Figure 6). The difference observed at the mutant D266A/D284A receptor is not as great as that previously observed with icatibant (see above), and we consider that this is due to the buried interaction of MEN16132 within the TM receptor region provided by TM3, 6 and 7 (see above) and to the fact that FR190997 interacts with some residues (i.e.…”

Effect of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate of bradykinin-induced smooth muscle contraction in the presence of calcium channel blockers

“…Взаємодія брадикініну зі специфічним поверхневим рецептором клітини викликає зміни рівнів цитоплазматичного кальцію із залученням різних систем, таких як фосфоліпаза С, простагландини, протеїнкінази та фосфоліпаза А 2 . Розвиток сучасної органічної хімії дозволяє синтезувати антагоністи непептидної природи, що потенційно можуть застосовуватись як блокатори активності кінін-калікреїнової системи кишечника (Kam Ro et al, 2005;Fattori et al, 2007). Для створення речовин, здатних взаємодіяти з рецепторним апаратом кінін-калікреїнової системи, використовують бензодіазепінове ядро, здатне набувати структури β-згину біологічно активних пептидів.…”

An Efficient Methodology for the Synthesis of 1-(Trimethylammoniummethyl)cyclohexaneacetic Acid Iodide: A Trimethylammonium Iodide Salt of Gabapentin

“…N-quaternization of the amino group present in gabapentin 1 was initially investigated using methods reported to be successful for the N-methylation of GABA. For instance, treatment of gabapentin 1 with either methyl iodide and potassium bicarbonate, 7 or dimethyl sulphate and sodium hydroxide, 8 did not furnish the respective trimethylammonium salt 2 or 3, presumably due to the low basicity of the amino group. 1-(Dimethylaminomethyl)cyclohexaneacetic acid (4a) was subsequently prepared via reductive alkylation of 1 with aqueous formaldehyde in the presence of 10% Pd/C and H 2 gas at 15 psi to increase the basicity of the amino group.…”

“…1-(Dimethylaminomethyl)cyclohexaneacetic acid (4a) was subsequently prepared via reductive alkylation of 1 with aqueous formaldehyde in the presence of 10% Pd/C and H 2 gas at 15 psi to increase the basicity of the amino group. 8 However, reaction of 4a with methyl iodide 5 to produce the trimethylammonium salt 2 did not proceed. The failure of this reaction is attributed to the likelihood that the aminoacid 4a exists as a non-reactive zwitterionic species.…”