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

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‐difluorophen...