Studies on Novel Bone Resorption Inhibitors. II. Synthesis and Pharmacological Activities of Fused Aza-heteroarylbisphosphonate Derivatives.

Takeuchi, Makoto; Sakamoto, Shunichi; Kawamuki, Kousei; Kurihara, Hiroyuki; Nakahara, Hideaki; Isomura, Yasuo

doi:10.1248/cpb.46.1703

Cited by 39 publications

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“…In Figure 3B-D, we present results for three more pairs of bisphosphonates in which the effects of minor chemical changes are known to abrogate bisphosphonate effects on bone resorption and/or FPPS inhibition. Their structures are shown below: For example, the drugs minodronate (3), olpadronate (31), and risedronate (8) (top row) are all potent γδ T cell activators ( Figure 3B-D), bone resorption drugs, 35,39,45,46 and FPPS inhibitors. 25,45 However, moving the position of ring alkylation in 3 (to 51), replacing the OH group by an NH 2 in 31 (to 49), or adding a CH 2 group to 8 (to 47) (bottom row) results in the loss of essentially all activity in γδ T cell activation ( Figure 3B-D), bone resorption, 39,45,46 or FPPS inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…Their structures are shown below: For example, the drugs minodronate (3), olpadronate (31), and risedronate (8) (top row) are all potent γδ T cell activators ( Figure 3B-D), bone resorption drugs, 35,39,45,46 and FPPS inhibitors. 25,45 However, moving the position of ring alkylation in 3 (to 51), replacing the OH group by an NH 2 in 31 (to 49), or adding a CH 2 group to 8 (to 47) (bottom row) results in the loss of essentially all activity in γδ T cell activation ( Figure 3B-D), bone resorption, 39,45,46 or FPPS inhibition. 25,45 While these observations do not, in and of themselves, prove a causal link between FPPS inhibition and γδ T cell activation (as suggested by Thompson et al 19 ), the effects of minor structural changes are very pronounced and do suggest the possibility of such a relationship.…”

Section: Resultsmentioning

confidence: 99%

“…The syntheses of the bisphosphonates investigated (3-51, 53-67; Figures 1 and 2) used methods which are described in more detail elsewhere. 25,26,[35][36][37][38][39][40][41][42] 52 was prepared using the following route: 31 and 49 were from Gador S.A. (Buenos Aires) and were a gift from Teresita Bellido at the University of Arkansas for Medical Sciences. Most compounds investigated were available from previous work.…”

Section: Methodsmentioning

confidence: 99%

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A Quantitative Structure−Activity Relationship and Pharmacophore Modeling Investigation of Aryl-X and Heterocyclic Bisphosphonates as Bone Resorption Agents

Kotsikorou

Oldfield

2003

J. Med. Chem.

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γδ T cells are the first line of defense against many infectious organisms and are also involved in tumor cell surveillance and killing. They are stimulated by a broad range of small, phosphorus-containing antigens (phosphoantigens) as well as by the bisphosphonates commonly used in bone resorption therapy, such as pamidronate and risedronate. Here, we report the activation of γδ T cells by a broad range of bisphosphonates and develop a pharmacophore model for γδ T cell activation, in addition to using a comparative molecular similarity index analysis (CoMSIA) approach to make quantitative relationships between γδ T cell activation by bisphosphonates and their three-dimensional structures. The CoMSIA analyses yielded R 2 values of ∼0.8-0.9 and q 2 values of ∼0.5-0.6 for a training set of 45 compounds. Using an external test set, the activities (IC 50 values) of 16 compounds were predicted within a factor of 4.5, on average. The CoMSIA fields consisted of ∼40% hydrophobic, ∼40% electrostatic, and ∼20% steric interactions. Since bisphosphonates are known to be potent, nanomolar inhibitors of the mevalonate/isoprene pathway enzyme farnesyl pyrophosphate synthase (FPPS), we also compared the pharmacophores for γδ T cell activation with those for FPPS inhibition, using the Catalyst program. The pharmacophores for γδ T cell activation and FPPS inhibition both consisted of two negative ionizable groups, a positive charge feature and an endocyclic carbon feature, all having very similar spatial dispositions. In addition, the CoMSIA fields were quite similar to those found for FPPS inhibition by bisphosphonates. The activities of the bisphosphonates in γδ T cell activation were highly correlated with their activities in FPPS inhibition: R ) 0.88, p ) 0.002, versus a human recombinant FPPS (N ) 9 compounds); R ) 0.82, p < 0.0001, for an expressed Leishmania major FPPS (N ) 45 compounds). The bisphosphonate γδ T cell activation pharmacophore differs considerably, however, from that reported previously for γδ T cell activation by phosphoantigens (Gossman, W.; Oldfield, E. J. Med. Chem. 2002, 45, 4868-4874), suggesting different primary targets for the two classes of compounds. The ability to quite accurately predict the activity of bisphosphonates as γδ T cell activators by using 3D QSAR techniques can be expected to help facilitate the design of additional bisphosphonates for potential use in immunotherapy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A Quantitative Structure−Activity Relationship and Pharmacophore Modeling Investigation of Aryl-X and Heterocyclic Bisphosphonates as Bone Resorption Agents

Kotsikorou

Oldfield

2003

J. Med. Chem.

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“…7) In contrast, large T m increases were observed when second-and third-generation BPs (N-BPs) were mixed with the IPP/FPPS complex. In particular, the addition of third-generation BPs such as risedronate, zoledronate, and minodronate 38) was found to induce T m increases of almost 20°C. These results clearly indicate favorable binding affinities of these third-generation N-BPs against FPPS.…”

Section: Resultsmentioning

confidence: 99%

Thermodynamic Evaluation of the Binding of Bisphosphonates to Human Farnesyl Pyrophosphate Synthase

Kawasaki

Sekiguchi

Kawasaki

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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Bisphosphonates (BPs) are the drug of choice for treating bone diseases such as osteoporosis, Paget's disease, and metastatic bone disease. BPs with nitrogen-containing side chains (N-BPs) are known to act as inhibitors for farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway. In this study, we evaluated the effect of different side chains on the binding affinity of BPs to human FPPS using calorimetric techniques. Differential scanning calorimetry (DSC) was used to determine the thermal unfolding of FPPS in the presence of BPs. The addition of a series of clinically available BPs increased the structural stability of human FPPS by preferential binding, as indicated by an increase in the FPPS unfolding temperature. The magnitude of the increase was correlated with in vivo antiresorptive efficacy, suggesting that the stabilization of FPPS underlies the inhibitory effect of the BPs. Isothermal titration calorimetry (ITC) experiments were performed to evaluate the binding thermodynamics of BPs against human FPPS. Analysis of the binding energetics revealed that over 30 years of optimization practiced by different pharmaceutical companies has enhanced the enthalpic contribution as well as binding affinity of BPs. The larger enthalpic contribution observed for newer, more potent BPs derives from both improved hydrogen bonding interactions and shape complementarity based on comparisons of our results with available structure information.Key words isothermal titration calorimetry; thermodynamics; drug discovery; enthalpy; differential scanning calorimetry Osteoporosis is a bone disease which leads to increased bone fragility and fracture risk. In osteoporosis, bone mineral density is reduced, bone microarchitecture deteriorates, and both the amount and variety of proteins in the bone are altered. The most common cause of this disease is increased bone turnover with excessive bone resorption that exceeds bone formation. Bisphosphonates (BPs) are a class of drugs widely used to treat diseases characterized by bone resorption, such as osteoporosis, Paget's disease, and metastatic bone disease.1-4) The two phosphate groups in the P-C-P structure of BPs are known to be important for BP interaction with a molecular target in the osteoclast and for the high affinity to bone mineral, both of which are required for BPs to inhibit bone resorption. [4][5][6] As shown in Fig. 1, side chains attached to the central carbon of the P-C-P allow for a wide range of possible chemical structures of clinically available drugs.3) However, while a wide variety of side chain structures has evolved from 30 years of research and development at different pharmaceutical companies, what underlies progression towards quality compounds in terms of thermodynamics of binding to a target remains unclear.First-generation BPs such as etidronate and clodronate have non-nitrogenous (non-N) side chains and act as pyrophosphate analogues. These non-N-BPs are metabolized to non-hydrolyzable cytotoxic ATP analogues that accumulate intr...

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“…Minodronate is a third generation BP originally developed at Astellas Pharma which was approved and launched in 2009 in Japan as an oral treatment for osteoprosis. Minodronate was synthesized by a team lead by one of the authors (M. Takeuchi) and has been shown to have 100-to 1000-fold stronger bone resorption activity than pamidronate [13]. Although minodronate shows the strongest activity among BPs, the reason for its strong activity remains unclear.…”

Section: Resultsmentioning

confidence: 99%

Density functional theory calculation of interaction between bisphosphate and farnesyl pyrophosphate synthase

et al. 2010

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Bisphosphonates (BPs) are the most widely used and effective treatment for osteoporosis and Pagets disease of the bone. To date, a number of BPs-namely alendronate, risedronate, and minodronate-have been launched to market. Nitrogen-BPs (N-BPs) act by inhibiting the enzyme farnesyl pyrophosphate synthase (FPPS), and several crystal structures of complexes between FPPS and N-BPs have been identified. Understanding the physical basis of the binding between proteins and small molecules is an important goal in both medicinal chemistry and structural biology. Here, we conducted density functional theory calculations for BPs and their surrounding residues and were able to successfully reproduce experimental results qualitatively. In addition, we found that both the side chain and backbone of Phe 99 are important for binding between minodronate and FPPS, suggesting that the strong activity of minodronate comes from its interaction with Phe 99, which alendronate and risedronate lack.

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Studies on Novel Bone Resorption Inhibitors. II. Synthesis and Pharmacological Activities of Fused Aza-heteroarylbisphosphonate Derivatives.

Cited by 39 publications

References 0 publications

A Quantitative Structure−Activity Relationship and Pharmacophore Modeling Investigation of Aryl-X and Heterocyclic Bisphosphonates as Bone Resorption Agents

A Quantitative Structure−Activity Relationship and Pharmacophore Modeling Investigation of Aryl-X and Heterocyclic Bisphosphonates as Bone Resorption Agents

Thermodynamic Evaluation of the Binding of Bisphosphonates to Human Farnesyl Pyrophosphate Synthase

Density functional theory calculation of interaction between bisphosphate and farnesyl pyrophosphate synthase

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