Structure–activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors

Abstract

A structure-activity relationship study of dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo [1,5-a]pyrimidine ring were also examined by preparing and evaluating pyrrolo[1,2-a]pyrimidine and pyrazolo [1,5-a]pyridine derivatives. In addition, increased mouse liver microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine. Finally, an optimized compound 13 (LDN-193189 or DM-3189) demonstrated moderate pharmacokinetic characteristics (e.g. plasma t 1/2 = 1.6 h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition.Bone morphogenetic proteins (BMPs) are a group of > 25 protein ligands that comprise a subset of the transforming growth factor β (TGF-β) family. BMPs modulate a multitude of biological processes, including bone and cartilage formation during embryogenesis. 1a However, they are also intimately involved with numerous nonosteogenic developmental and physiological processes throughout adulthood as well as several pathological conditions. BMPs bind to two classes of cell surface bone morphogenetic protein receptors (BMPR-I and BMPRII). 1a The BMPR-I receptor class consists of three receptor types, activin receptor-like kinase-2 (ALK-2 or ActR-IA), ALK-3 (BMPR-IA) and ALK-6 (BMPR-IB). The BMPR-II receptor class is comprised of three receptor types, BMPR-II, ActR-IIA and ActR-IIB. Binding of BMPs results in the formation of heterotetrameric complexes containing two type I and two *To whom correspondence should be addressed: Phone: 617-768-8640, Fax: 617-768-8606, E-mail: gcuny@rics.bwh.harvard.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Recently, dorsomorphin, 1, 7a, 11, 12 was discovered as an inhibitor of SMAD 1/5/8 phosphorylation by BMP type 1 receptors (ALK2, 3, and 6) utilizing a phenotypic screen to identify compounds that perturb embryonic dorsoventral axis formation. Furthermore, this inhibition was shown to decrease BMP-regulated hepatic hepcidin gene transcription, leading to increased iron levels in vivo. 7a However, 1 only demonstrated moderate inhibition of SMAD 1/5/8 phosphorylation by BMPR-I with an IC50 ~ 0.5 µM and lacks metabolic stability. Herein, we describe the results of a structu...

IdGene Regulation and Function in the Prosensory Domains of the Chicken Inner Ear: A Link between Bmp Signaling andAtoh1

“…This is consistent with the fast turnover of the Id mRNA and protein which have reported half-lives of 20 -60 min, depending on the cell type (Deed et al, 1996;Bounpheng et al, 1999;Norton, 2000). Dorsomorphin specifically blocks the phosphorylation of R-Smad mediated by type I Bmp-receptors without affecting other signaling pathways that can be activated by Bmps (Anderson and Darshan, 2008;Cuny et al, 2008;Hao et al, 2008;Yu et al, 2008). This suggests that Id expression in the prosensory domains of the early otocyst depends strictly on the steady activation of the Bmpinduced Smad signaling pathway.…”

Manipulation of the hepcidin pathway for therapeutic purposes

“…LDN-193189 is a derivative of dorsomorphin, a small-molecule inhibitor of the BMP pathway, and it specifically antagonizes BMP receptor isotypes ALK2 and ALK3. 76 Theurl et al used the rat PG-APS model of anemia of inflammation, and starting at three weeks after PG-APS injection administered LDN-193189 every other day for four weeks. This regimen decreased hepcidin, increased serum iron and effectively reversed anemia.…”

Simple vertebrate models for chemical genetics and drug discovery screens: Lessons from zebrafish and Xenopus

“…On the basis of the latter findings, dorsomorphin has been suggested as a promising lead compound for the treatment of anemia in chronic disease. Furthermore, preclinical studies of dorsomorphin and its subsequently developed more potent and specific derivatives (Cuny et al, 2008) have also suggested a rational therapy to treat fibrodysplasia ossificans progressiva (FOP), a congenital disorder of progressive and widespread postnatal ossification of soft tissues, and other heterotopic ossification syndromes associated with excessive BMP signaling (Yu et al, 2008a).…”