Design and synthesis of an orally active macrocyclic neutral endopeptidase 24.11 inhibitor

Abstract

A potent macrocyclic inhibitor of neutral endopeptidase (NEP) 24.11 was designed using a computer model of the active site of thermolysin. This 10-membered ring lactam represents a general mimic for any hydrophobic dipeptide in which the two amino acid side chains bind to an enzyme in a contiguous orientation. The parent 10-membered ring lactam was synthesized and exhibited excellent potency as an NEP 24.11 inhibitor (IC50 = 3 nM). In order to improve oral bioavailability, various functionality was attached to the macrocycle. These modifications lead to CGS 25155, an orally active NEP 24.11 inhibitor that slows down the degradation of the cardiac hormone atrial natriuretic factor, producing a lowering of blood pressure in the DOCA-salt rat model of hypertension.

Constraining Cyclic Peptides To Mimic Protein Structure Motifs

“…27). [31] Such macrocycles feature functionalized side chains of Tyr (e.g. 8, 9, 20, 26, 27), His (12), Glu (13), Ser (14), Phe (15,16), Lys (17), Cys (19), as well as Thr, Trp, Arg, Orn, Asp, Pro, Asn and derivatives.…”

“…There is a vast chemical literature for b-and g-turn subtypes [3][4][5]33] classified by variable phi/psi angles. Many small molecule turn mimics are known with potent biological [24][25][26][27][28][29][30][31][32] activities, and some have been developed into drugs. [5,33] Cyclization of peptides has been the most common method used to stabilize turns.…”

“…An antagonist (84) of the oncogenic NOTCH 1 transcription factor ternary complex was developed. The 15residue peptide from MAML1 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] blocked full length MAML1 binding to the ternary complex, suppressed NOTCH-1 signalling and had anti-leukemic activity in vivo. [99] Inhibitors of the p53-hDM2/hDMX interaction have been developed utilizing i!i + 7 staples (85)(86)(87).…”

Protein Crystallography and Drug Discovery

“…An analysis of the conformation of related compounds in the Cambridge data bank can guide this process [122], and ab initio calculations are often useful [122,123]. Introduction of conformational restraints through (macro)cyclization [124] or the introduction of rigid linkers [125] is another strategy that has been successfully used in many cases to minimize entropic penalties. Small-molecule ligands frequently adopt an extended conformation in the bound state [121].…”

The Synthesis of Macrocycles for Drug Discovery

“…For example, construction of the scaffold for the (208) and related analogues was achieved utilizing two successive one atom ring expansions from cyclooctanone. 318 Subsequent transformations then resulted in the 10-membered ring target molecules (Figure 11.16, reagents for ring expansion noted). In another such process, nitrogen insertion/ring expansion of cyclic ketones provided either macrolactams (209) or macrolactones (210), with the relative proportions dependent on the ring size of the precursor and the pH of the reaction medium (Figure 11.16, reagents common for both products indicated).…”