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

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)=1.6h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition.

[1]  R. Campbell,et al.  Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. , 2004, Bioorganic & medicinal chemistry letters.

[2]  O. Eickelberg,et al.  Transforming growth factor beta/bone morphogenic protein signaling in pulmonary arterial hypertension: remodeling revisited. , 2007, Trends in cardiovascular medicine.

[3]  O. Baudoin.  New approaches for decarboxylative biaryl coupling. , 2007, Angewandte Chemie.

[4]  J. Shipman,et al.  Design and synthesis of 3,7-diarylimidazopyridines as inhibitors of the VEGF-receptor KDR. , 2004, Bioorganic & medicinal chemistry letters.

[5]  W. Jiang,et al.  Bone morphogenetic proteins and their receptor signaling in prostate cancer. , 2007, Histology and histopathology.

[6]  T. Engler,et al.  An improved method for direct conversion of heteroaryl-aldehydes to heteroaryl-acetonitriles , 2003 .

[7]  Charles C Hong,et al.  Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. , 2008, Nature chemical biology.

[8]  W. F. Hoffman,et al.  Optimization of a pyrazolo[1,5-a]pyrimidine class of KDR kinase inhibitors: improvements in physical properties enhance cellular activity and pharmacokinetics. , 2002, Bioorganic & medicinal chemistry letters.

[9]  P. Knaus,et al.  Signal transduction of bone morphogenetic protein receptors. , 2004, Cellular signalling.

[10]  Y. Yamashita,et al.  Synthesis and reactions of 3,3′-dibromodihydrodipyrrins , 1997 .

[11]  Claude Y. Legault,et al.  Highly efficient synthesis of O-(2,4-dinitrophenyl)hydroxylamine. Application to the synthesis of substituted N-benzoyliminopyridinium ylides. , 2003, The Journal of organic chemistry.

[12]  Françoise Gellibert,et al.  Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-beta type I receptor inhibitors. , 2004, Journal of medicinal chemistry.

[13]  Adam R. Urbach,et al.  Toward an Understanding of the Chemical Etiology for DNA Minor‐Groove Recognition by Polyamides , 2002 .

[14]  C. Lindsley,et al.  Microwave-assisted protocols for the expedited synthesis of pyrazolo[1,5-a] and [3,4-d]pyrimidines , 2008 .

[15]  Margaret S. Wu,et al.  Role of AMP-activated protein kinase in mechanism of metformin action. , 2001, The Journal of clinical investigation.

[16]  H. Beppu,et al.  Bone Morphogenetic Protein (BMP) Type II Receptor Deletion Reveals BMP Ligand-specific Gain of Signaling in Pulmonary Artery Smooth Muscle Cells* , 2005, Journal of Biological Chemistry.

[17]  D. Huylebroeck,et al.  New intracellular components of bone morphogenetic protein/Smad signaling cascades , 2003, FEBS letters.

[18]  C. Minetti,et al.  Potential drug targets within bone morphogenetic protein signaling pathways. , 2007, Current opinion in pharmacology.

[19]  L. Goodnough,et al.  Anemia of chronic disease. , 2005, The New England journal of medicine.

[20]  In Ho Choi,et al.  A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva , 2006, Nature Genetics.

[21]  W. F. Hoffman,et al.  Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines: a new class of KDR kinase inhibitors. , 2002, Bioorganic & medicinal chemistry letters.

[22]  Yin Xia,et al.  Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. , 2007, The Journal of clinical investigation.

[23]  Richard Svensson,et al.  Introduction to in vitro estimation of metabolic stability and drug interactions of new chemical entities in drug discovery and development. , 2006, Pharmacological reports : PR.

[24]  Jerry Kaplan,et al.  Hepcidin regulation: ironing out the details. , 2007, The Journal of clinical investigation.

[25]  P. Billings,et al.  Dysregulated BMP Signaling and Enhanced Osteogenic Differentiation of Connective Tissue Progenitor Cells From Patients With Fibrodysplasia Ossificans Progressiva (FOP) , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[26]  P. Gmeiner,et al.  Rationally based efficacy tuning of selective dopamine d4 receptor ligands leading to the complete antagonist 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213). , 2001, Journal of medicinal chemistry.

[27]  Ruth Lehr,et al.  Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5). , 2002, Journal of medicinal chemistry.

[28]  M. Bailey,et al.  Unexpected intermolecular pd-catalyzed cross-coupling reaction employing heteroaromatic carboxylic acids as coupling partners. , 2006, Journal of the American Chemical Society.

[29]  W. Linehan,et al.  Decreased expression of bone morphogenetic protein (BMP) receptor type II correlates with insensitivity to BMP-6 in human renal cell carcinoma cells. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[30]  Y. Tamura,et al.  Effects of 3-substituents upon orientation in the 1,3-dipolar cyclo-addition reaction between 3-substituted pyridine N-imides and ethyl propiolate: syntheses of ethyl 4- and 6-substituted pyrazolo[1,5-a]-pyridine-3-carboxylates , 1975 .

[31]  Guojun Deng,et al.  Synthesis of Biaryls via Catalytic Decarboxylative Coupling , 2006, Science.

[32]  Dong Liu,et al.  Dosage-dependent requirement of BMP type II receptor for maintenance of vascular integrity. , 2007, Blood.