title: Identification of novel 2-((1-(benzyl(2-hydroxy-2-phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)benzoic acid analogues as BMP-2 stimulators.
abstract: The synthesis and SAR studies of 10 new chemical entities (NCEs) that have shown BMP-2 stimulation and osteoblast differentiation are reported. Among these, 2-((1-(benzyl(2-hydroxy-2-phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)benzoic acid (11) was the most effective while its analogue 13 also showed good activity in inducing osteoblast BMP-2 production. Compound 11 induced osteoblast differentiation in vitro, and this effect was abrogated by a physiological BMP-2 inhibitor, noggin. It also exhibited dose dependent increase in nascent bone formation (2.16- and 3.12-fold more than the control at 1 and 5 mg/kg dose, respectively) at the fracture site in rats. At the maximum osteogenic concentration, compound 11 significantly inhibited osteoblastic proteosomal activity. This compound was safe, as it had no effect on BMP synthesis in cardiovascular tissue.
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, 226001, India.
authors.forename: Vishal M
authors.initials: VM
authors.lastname: Balaramnavar
authors.forename: Imran A
authors.initials: IA
authors.lastname: Khan
authors.forename: Jawed Akhtar
authors.initials: JA
authors.lastname: Siddiqui
authors.forename: Mohd Parvez
authors.initials: MP
authors.lastname: Khan
authors.forename: Bandana
authors.initials: B
authors.lastname: Chakravarti
authors.forename: Kunal
authors.initials: K
authors.lastname: Sharan
authors.forename: Gaurav
authors.initials: G
authors.lastname: Swarnkar
authors.forename: Namrata
authors.initials: N
authors.lastname: Rastogi
authors.forename: H H
authors.initials: HH
authors.lastname: Siddiqui
authors.forename: Durga Prasad
authors.initials: DP
authors.lastname: Mishra
authors.forename: Naibedya
authors.initials: N
authors.lastname: Chattopadhyay
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saxena
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000096:biosynthesis*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D017102:Fracture Healing / Q000187:drug effects; D050723:Fractures, Bone / Q000188:drug therapy / Q000503:physiopathology; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010795:Phthalic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: C577111:2-((1-oxo-1-(phenethylamino)-3-phenylpropan-2-yl)carbamoyl)benzoic acid; D055396:Bone Morphogenetic Protein 2; D010795:Phthalic Acids; D061988:Proteasome Inhibitors; D010649:Phenylalanine