Solid phase assisted synthesis of HIV-1 protease inhibitors. Expedient entry to unsymmetrical substitution of aC₂symmetric template

Abstract

A solid phase synthesis has been developed leading up to unsymmetrical HIV-1 protease inhibitors that are not readily available by conventional solution phase chemistry (18a-g). To prepare these compounds the hydroxyl group of (1S,2R)-(-)-cis-1-phthalimido-2-indanol (3) was coupled to a Merrifield resin via a dihydropyrane linker. Cleavage of the phthalimido protecting group and reaction of the liberated amine with the bis-activated symmetrical diacid 15 resulted in the resin bound amide 16. Coupling of 16 with amino acids and amines followed by hydrolysis produced the desired unsymmetrical products 18a-g from which potent HIV-1 protease inhibitors were identified, e.g., 18e (k i = 0.1 nM), 18a (k i = 0.2 nM) and 18c (k i = 2 nM).Résumé : On a mis au point une synthèse en phase solide qui permet d'obtenir des inhibiteurs non symétriques de protéase HIV-1 (18a-g) qu'il est difficile d'obtenir par la chimie conventionnelle en solution. Dans cette synthèse, on couple le groupement hydroxyle du (1S,2R)-(-)-cis-1-phtalimido-indan-2-ol (3) à une résine de Merrifield à l'aide d'une liaison avec un dihydropyrane. Après clivage du groupe phtalimido protecteur et réaction de l'amine libérée avec le diacide symétrique 15 doublement activé, on obtient l'amide 16 lié à la résine. Le couplage de 16 avec des acides aminés ou avec des amines suivi d'une hydrolyse permet d'obtenir les produits non symétriques désirés 18a-g à partir desquels il a été possible d'identifier de puissants inhibiteurs de protéase de l'HIV-1, par exemple 18e (k i = 0,1 nM), 18a (k i = 0,2 nM) et 18c (k i = 2 nM).

Oxetanes: Recent Advances in Synthesis, Reactivity, and Medicinal Chemistry

“…Samuelsson and co-workers 385 described a series of HIV-1 protease inhibitors with a number of different substituents containing hydrogen-bond acceptors. The isopropyl group from the L-Val methyl side chain, reported previously, 386 was replaced with a 3-oxetane (250), an ethoxymethyl, and a 1methyl-substituted ethoxymethyl in order to "extend" a H-bond acceptor from the original position of the isopropyl (Figure 24b). This was designed to promote a positive interaction with the nitrogen of the Asp-30 residue of the HIV-1 protease backbone.…”

Design and Synthesis of Protein Superfamily-Targeted Chemical Libraries for Lead Identification and Optimization

“…Oscarsson and co-workers have developed a solid phase synthesis of unsymmetrical HIV-1 protease inhibitors, among which highly potent inhibitors were identified, including (156) [213].…”

“…16) Poirier and co-workers have synthesized a variety of steroidal HSD inhibitors using parallel synthesis [263]. Variations to the 3-(α,β), and 17-β positions of the core scaffolds (209)- (213) were examined, notably with primary amine residues, which were subsequently derivatized with a range of electrophiles. These compounds displayed good activity against HSD, with IC 50 values ranging from 50 to 150 nM.…”

cis-1-Amino-2-indanol in Drug Design and Applications to Asymmetric Processes

“…[21][22][23][24][25][26] Continuing efforts in the search for more effective protease inhibitors led to the discovery of several drug candidates which displayed comparable enzyme-inhibitory effects and antiviral potencies to Indinavir. [27][28][29][30][31][32][33][34][35][36] In particular, Samuelsson and co-workers [33][34][35][36] designed a new C 2 -symmetric HIV-PR inhibitor, on the basis of X-ray crystal structures, which indicated that the HIV-protease existed as a C 2 -symmetric dimer. The peptidomimetic scaffold of this new class of inhibitors was based on D-mannitol and duplication of the C-terminus.…”