Differentiation of skeletal osteogenic progenitor cells to osteoblasts with 3,4-diarylbenzopyran based amide derivatives: Novel osteogenic agents

• Published in: European journal of medicinal chemistry Vol. 121; pp. 82 - 99
• Main Authors: Gupta, Atul, Ahmad, Imran, Kureel, Jyoti, John, Aijaz A., Sultan, Eram, Chanda, Debabrata, Agarwal, Naresh Kumar, Alauddin, Wahajuddin, Prabhaker, S., Verma, Amita, Singh, Divya
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 04.10.2016; Elsevier
• Subjects: Amides - chemistry; Amides - pharmacokinetics; Amides - pharmacology; Animals; Antiosteoporotic; Benzopyran; Benzopyrans - chemistry; Benzopyrans - pharmacokinetics; Benzopyrans - pharmacology; Biological Availability; Cell Differentiation - drug effects; Chemistry, Medicinal; Estrogen; Estrogen Receptor beta - metabolism; Isoflavone; Life Sciences & Biomedicine; Mice; Mice, Inbred BALB C; Osteoblasts - cytology; Osteogenesis - drug effects; Osteogenic; Osteoporosis - chemically induced; Pharmacology & Pharmacy; Science & Technology; Stem Cells - cytology; Structure-Activity Relationship; Isoflavone; Osteogenic; Benzopyran; Antiosteoporotic; Estrogen; IPRIFLAVONE; MECHANISMS; GENISTEIN; BONE-RESORPTION; BREAST-CANCER; ISOFLAVONES; POSTMENOPAUSAL OSTEOPOROSIS; EQUOL; DAIDZEIN; ESTROGEN-RECEPTOR-ALPHA
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.05.023

A series of 3,4-diarylbenzopyran based amide derivatives was synthesized and evaluated for osteogenic activity in in vitro and in vivo models of osteoporosis. Compounds 17a, 21b–c and 22a–b showed significant osteogenic activity in osteoblast differentiation assay. Among the synthesized compounds, 22b was identified as lead molecule which showed significant osteogenic activity at 1 pM concentration in osteoblast differentiation assay and at 1 mg kg−1 body weight dose in estrogen deficient balb/c mice model. In vitro bone mineralization and expression of osteogenic marker genes viz BMP-2, RUNX-2, OCN, and collagen type 1 further confirmed the osteogenic potential of 22b. Gene expression study for estrogen receptor α and β (ER-α and ER-β) in mouse calvarial osteoblasts (MCOs) unveiled that possibly 22b exerted osteogenic efficacy via activation of Estrogen receptor-β preferentially. In vivo pharmacokinetic, estrogenicity and acute toxicity studies of 22b showed that it had good bioavailability and was devoid of uterine estrogenicity at 1 mg kg−1 and inherent toxicity up to 1000 mg kg−1 body weight dose respectively. [Display omitted] •3,4-diarylbenzopyran based amide derivatives as novel osteogenic agents were identified.•22b showed osteogenic activity at 1 pM in osteoblast differentiation assay and at 1 mg kg−1 body weight dose in estrogen deficient balb/c mice model.•Bone mineralization and expression of osteogenic marker genes confirmed osteogenic potential of 22b.•22b showed good bioavailability and devoid of uterine estrogenicity at 1 mg kg−1in-vivo.•22b had no inherent toxicity up to 1000 mg kg−1 body weight dose in in-vivo model respectively.