title: Cyclic HIV protease inhibitors: design and synthesis of orally bioavailable, pyrazole P2/P2' cyclic ureas with improved potency.
abstract: Highly potent HIV-1 protease (HIVPR) inhibitors have been designed and synthesized by introducing bidentate hydrogen-bonding oxime and pyrazole groups at the meta-position of the phenyl ring on the P2/P2' substituents of cyclic ureas. Nonsymmetrical cyclic ureas incorporating 3(1H)-pyrazolylbenzyl as P2 and hydrophilic functionalities as P2' show potent protease inhibition and antiviral activities against HIV and have good oral bioavailabilities. The X-ray structure of HIVPR.10A complex confirms that the two pyrazole rings of 10A form bidentate hydrogen bonds with the side-chain oxygen (C=O) and backbone nitrogen (N-H) of Asp30/30' of HIVPR.
authors.affiliation: Chemical and Physical Sciences, The DuPont Merck Pharmaceutical Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Han
authors.forename: C H
authors.initials: CH
authors.lastname: Chang
authors.forename: R
authors.initials: R
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Ru
authors.forename: P K
authors.initials: PK
authors.lastname: Jadhav
authors.forename: P Y
authors.initials: PY
authors.lastname: Lam
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D001381:Azepines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D008958:Models, Molecular; D011720:Pyrazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C112578:(4R,5S,6S,7R)-hexahydro-5,6-dihydroxy-1,3-bis((3-(1H-pyrazol-3-yl)phenyl)methyl)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one; D019380:Anti-HIV Agents; D001381:Azepines; D017320:HIV Protease Inhibitors; D011720:Pyrazoles