α,α-Cyclic aminoacids as useful scaffolds for the preparation of hNK2 receptor antagonists

Design, Synthesis and Late‐Stage Modification of Indane‐Based Peptides via [2+2+2] Cyclotrimerization

“…5H),3H),6.82 (bs,1H),5.20 (bs,1H),1H),3.94 (s,2H),3.70 (s,4H),3.49 (d,J = 16.1 Hz,1H),2H),3H), 1.41 (s, 9H), 0.91(t, J = 5.25 Hz, 6H) ppm, 13 C NMR (125 MHz, CDCl 3 ): δ 173. 6,173.2,155.0,141.4,140.4,140.3,140.1,129.1,128.7,128.1,127.9,126.3,125.6,125.3,124.9,124.8,80.8,67.2,52.4,51.1,41.9,41.6,29.9,28.4,24.9,23.1,21.9 ppm,HRMS…”

“…[4] Scheme 1 (1)(2)(3)(4)(5) shows various biologically active Aic containing molecules such as activated protein C (aPC, 2) inhibitor [5] and lymphocyte function-associated antigen-1 (LFA-1, 3) antagonists. [6] Over the years, Aic derivatives have attracted much attention as photo affinity labeling agents. [7] In 2007, Kowalczyk et al reported the effects of n-terminal part modification of arginine vasopressin analogues with Aic and one of the new peptides exhibited antidiuretic activity and thus being one of the most potent antidiuretic vasopressin analogues reported to date.…”

Structure−Activity Relationships of 6-Methyl-benzo[b]thiophene-2-carboxylic Acid (1-{(S)-1-Benzyl-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]butylcarbamoyl}cyclopentyl)amide, Potent Antagonist of the Neurokinin-2 Receptor

“…The human NK 2 receptor (hNK 2 ) has been identified and supported as a suitable target for development of novel drugs to be used for the treatment of a number of diseases in the respiratory, gastrointestinal, and genitourinary tracts and in the CNS. As part of a project aimed at the identification of a series of small, orally available antagonists for the hNK 2 , starting from one of our capped dipeptide libraries, we were able to identify a number of molecules with subnanomolar binding affinity for the hNK 2 receptor . All the molecules were characterized by a rigid core structure containing an α,α-cyclopentaneglycine fragment.…”

Discovery of a New Series of Potent and Selective Linear Tachykinin NK2 Receptor Antagonists

“…6 We present now the synthesis and the structureactivity relationship (SAR) study of a series of new potent antagonists derived from a lead molecule previously obtained by the screening of original libraries (whose design and preparation with a parallel synthesis approach have been described elsewhere). 7 Library screening allowed us to identify the small molecule linear compound 1 (benzo[b]thiophene-2carboxylic acid {1-[1-(R)-(3-morpholin-4-ylpropylcarbamoyl)-2-phenylethylcarbamoyl]cyclopentyl}-amide, MEN14268) 8 (Figure 1), a simple and versatile structure with nanomolar binding affinity for the human NK 2 receptor. During the following lead optimization we decided, with the aim to keep complexity to a minimum, to consider only compounds with no more than a single chiral center and two aromatic rings.…”