Discovery of a new series of potent and selective linear tachykinin NK2 receptor antagonists.

Starting from 1 (MEN14268), a selective tachykinin NK2 receptor antagonist with an interesting in vitro pharmacological profile, a family of numerous antagonists was obtained through an optimization process focused on iterated structural modifications. The effects of the introduction of a wide variety of substituents on the lipophilic aromatic part of the molecule and the modulation of the structural constraint through the insertion of different achiral alpha,alpha-dialkylamino acids were investigated. In particular, aromatic and benzofused heteroaromatic moieties were introduced at the pseudo-N-terminal residue to replace the 2-benzothiophene moiety, and a systematic investigation of the best positioning of substituents onto the aromatic platform was reported for the benzothiophene core. Studies on the modulation of the length and the rigidity of the hydrophilic pseudo-C-terminal pendant are presented. Many heteroaliphatic groups are well tolerated by the receptor in this part of the ligand. The product 48f (MEN15596), bearing a methyl substituent on the benzothiophene and a tetrahydropyranylmethylpiperidine pendant, was finally selected for its good in vivo activity after intravenous, intraduodenal, and oral administration in guinea pigs.

Insertion of an aspartic acid moiety into cyclic pseudopeptides: synthesis and biological characterization of potent antagonists for the human Tachykinin NK-2 receptor.

A new series of monocyclic pseudopeptide tachykinin NK-2 receptor antagonists has been derived from the lead compound MEN11558. A synthesis for these molecules sharing the same intermediate was designed and performed. The replacement of the succinic moiety with an aspartic acid and the functionalization of its amino group with a wide variety of substituents led to very potent and selective NK-2 antagonists. Best results were obtained through the insertion in position 12 of an amino group with R configuration, linked by a short spacer to a saturated nitrogen heterocycle (morpholine, piperidine, or piperazine). The study led to compounds 54 and 57, endowed with high in vivo potency at very low doses and long duration of action in animal models of bronchoconstriction. In particular 54 and 57 completely inhibited NK-2 agonist induced bronchoconstriction in guinea pig after intratracheal administration at subnanomolar doses (ED(50) = 0.27 nmol/kg and 0.15 nmol/kg, respectively).

Modulation on C- and N-terminal moieties of a series of potent and selective linear tachykinin NK(2) receptor antagonists.

Herein we describe the synthesis of a series of new potent tachykinin NK(2) receptor antagonists by the modulation of the C- and N-terminal moieties of ibodutant (MEN 15596, 1). The N-terminal benzo[b]thiophene ring was replaced by different substituted naphthalenes and benzofurans, while further modifications were evaluated at the C-terminal tetrahydropyran moiety. Most compounds demonstrated a high affinity for the human NK(2) receptor and high in vitro antagonist potency, indicating that a wide range of substituents at both termini can be incorporated in the molecule without detrimental effects on the interactions with the NK(2) receptor. Selected compounds were tested in vivo confirming their activity as NK(2) antagonists. In particular, after both iv and id administration to guinea pig, compound 61 b was able to antagonize NK(2)-induced colonic contractions with a potency and duration-of-action fully comparable to the reference compound 1 (MEN 15596, ibodutant).

Insertion of 2-carboxysuccinate and tricarballylic acid fragments into cyclic-pseudopeptides: new antagonists for the human tachykinin NK-2 receptor.

A series of cyclic pseudopeptides were synthesized containing the sequence -Trp-Phe-(D)-PhePsiCH2NH-, the terminal ends of which were bound to 2-carboxy succinate or enantiomerically enriched tricarballylic acid to give the final cyclic structures. These two molecules and their subsequent derivatives were screened for h-NK2 receptor binding and functional antagonist activity on the rabbit urinary bladder.