Design of Highly Potent, Dual‐Acting and Central‐Nervous‐System‐Penetrating HIV‐1 Protease Inhibitors with Excellent Potency against Multidrug‐Resistant HIV‐1 Variants

• Published in: ChemMedChem Vol. 13; no. 8; pp. 803 - 815
• Main Authors: Ghosh, Arun K., Rao, Kalapala Venkateswara, Nyalapatla, Prasanth R., Kovela, Satish, Brindisi, Margherita, Osswald, Heather L., Sekhara Reddy, Bhavanam, Agniswamy, Johnson, Wang, Yuan‐Fang, Aoki, Manabu, Hattori, Shin‐ichiro, Weber, Irene T., Mitsuya, Hiroaki
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 23.04.2018; Wiley Subscription Services, Inc; ChemPubSoc Europe
• Subjects: Animals; antiviral agents; BASIC BIOLOGICAL SCIENCES; Brain - metabolism; brain penetration; Carbamates - chemistry; Carbamates - pharmacokinetics; Carbamates - pharmacology; Cell Line; Central nervous system; Chemistry, Medicinal; Crystal structure; Crystallography, X-Ray; Design; Dimerization; Drug Design; Drug resistance; Halogenation; HIV; HIV Infections - drug therapy; HIV Infections - virology; HIV Protease - chemistry; HIV Protease - metabolism; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacokinetics; HIV Protease Inhibitors - pharmacology; HIV-1 - chemistry; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 protease; Human immunodeficiency virus; Humans; Life Sciences & Biomedicine; Ligands; Models, Molecular; Multidrug resistant organisms; Penetration resistance; Pharmacology & Pharmacy; Protease; Protease inhibitors; Proteinase inhibitors; Rats; Science & Technology; structure-based design; DIMERIZATION INHIBITION; DARUNAVIR; CCP4 SUITE; antiviral agents; brain penetration; COMPLEXES; DRUG-RESISTANCE; structure-based design; IN-VITRO; RESOLUTION CRYSTAL-STRUCTURES; REPLICATION; ASYMMETRIC EPOXIDATION; FLUORINE; drug resistance; HIV-1 protease
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.201700824

Herein we report the design, synthesis, X‐ray structural, and biological studies of an exceptionally potent HIV‐1 protease inhibitor, compound 5 ((3S,7aS,8S)‐hexahydro‐4H‐3,5‐methanofuro[2,3‐b]pyran‐8‐yl ((2S,3R)‐4‐((2‐(cyclopropylamino)‐N‐isobutylbenzo[d]thiazole)‐6‐sulfonamido)‐1‐(3,5‐difluorophenyl)‐3‐hydroxybutan‐2‐yl)carbamate). Using structure‐based design, we incorporated an unprecedented 6‐5‐5‐ring‐fused crown‐like tetrahydropyranofuran as the P2‐ligand, a cyclopropylaminobenzothiazole as the P2′‐ligand, and a 3,5‐difluorophenylmethyl group as the P1‐ligand. The resulting inhibitor 5 exhibited exceptional HIV‐1 protease inhibitory and antiviral potency at the picomolar level. Furthermore, it displayed antiviral IC50 values in the picomolar range against a wide panel of highly multidrug‐resistant HIV‐1 variants. The inhibitor shows an extremely high genetic barrier against the emergence of drug‐resistant variants. It also showed extremely potent inhibitory activity toward dimerization as well as favorable central nervous system penetration. We determined a high‐resolution X‐ray crystal structure of the complex between inhibitor 5 and HIV‐1 protease, which provides molecular insight into the unprecedented activity profiles observed. Crystal clear: We report the structure‐based design, synthesis, biological evaluation, and X‐ray structural studies of a series of exceptionally potent HIV‐1 protease inhibitors containing novel P1, P2, and P2′ ligands to interact with active site residues. Inhibitor 5 shows exceptional HIV‐1 inhibitory and antiviral potency at the picomolar level. An X‐ray structure of the inhibitor 5‐bound HIV‐1 protease complex provides molecular insight into the unprecedented activity profiles.