title: Design and synthesis of a series of (2R)-N(4)-hydroxy-2-(3-hydroxybenzyl)-N(1)- [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]butanediamide derivatives as potent, selective, and orally bioavailable aggrecanase inhibitors.
abstract: A pharmacophore model of the P1' site, specific for aggrecanase, was defined using the specificity studies of the matrix metalloproteinases and the similar biological activity of aggrecanase and MMP-8. Incorporation of the side chain of a tyrosine residue into compound 1 as the P1' group provided modest selectivity for aggrecanase over MMP-1, -2, and -9. A cis-(1S)(2R)-amino-2-indanol scaffold was incorporated as a tyrosine mimic (P2') to conformationally constrain 2. Further optimization resulted in compound 11, a potent, selective, and orally bioavailable inhibitor of aggrecanase.
authors.affiliation: The DuPont Pharmaceuticals Company, Chemical and Physical Sciences, Inflammatory Diseases Research, Drug Metabolism and Pharmacokinetics Division, Experimental Station, Wilmington, Delaware 19880-0500, USA. Wenqing.yao@dupontpharma.com
authors.forename: W
authors.initials: W
authors.lastname: Yao
authors.forename: Z R
authors.initials: ZR
authors.lastname: Wasserman
authors.forename: M
authors.initials: M
authors.lastname: Chao
authors.forename: G
authors.initials: G
authors.lastname: Reddy
authors.forename: E
authors.initials: E
authors.lastname: Shi
authors.forename: R Q
authors.initials: RQ
authors.lastname: Liu
authors.forename: M B
authors.initials: MB
authors.lastname: Covington
authors.forename: E C
authors.initials: EC
authors.lastname: Arner
authors.forename: M A
authors.initials: MA
authors.lastname: Pratta
authors.forename: M
authors.initials: M
authors.lastname: Tortorella
authors.forename: R L
authors.initials: RL
authors.lastname: Magolda
authors.forename: R
authors.initials: R
authors.lastname: Newton
authors.forename: M
authors.initials: M
authors.lastname: Qian
authors.forename: M D
authors.initials: MD
authors.lastname: Ribadeneira
authors.forename: D
authors.initials: D
authors.lastname: Christ
authors.forename: R R
authors.initials: RR
authors.lastname: Wexler
authors.forename: C P
authors.initials: CP
authors.lastname: Decicco
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001216:Asparagine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D004285:Dogs; D015195:Drug Design; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry; D020784:Matrix Metalloproteinase 8 / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; C438585:N-hydroxy-2-(cyclopropylmethylamino)-4-((2-hydroxyindan-1-yl)amino)-3-((3-hydroxyphenyl)methyl)-4-oxobutanamide; D011480:Protease Inhibitors; D001216:Asparagine; D010450:Endopeptidases; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; C083641:aggrecanase