Ian Bell - Academia.edu (original) (raw)
Papers by Ian Bell
Bioorganic & Medicinal Chemistry Letters, 2015
In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaff... more In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67nM), and selective compound (hERG IC50=19μM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold).
Journal of Medicinal Chemistry, 2001
The synthesis, structure-activity relationships, and biological properties of a novel series of i... more The synthesis, structure-activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with excellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of cell potency to intrinsic potency, compared with other known FTIs. It exhibited excellent potency against a range of tumor cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.
Journal of Medicinal Chemistry, 2002
A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synth... more A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.
Bioorganic & Medicinal Chemistry Letters, 2009
Rational modification of a previously identified spirohydantoin lead structure has identified a s... more Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K i = 40 pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.
Bioorganic & Medicinal Chemistry Letters, 2001
A series of amino acid-based linkers was used to investigate the effects of various substituents ... more A series of amino acid-based linkers was used to investigate the effects of various substituents upon the potency, pharmacokinetic properties, and conformation of macrocyclic farnesyl-protein transferase inhibitors (FTIs). As a result of the studies described herein, highly potent FTIs with improved pharmacokinetic profiles have been identified.
Bioorganic & Medicinal Chemistry Letters, 2006
Bioorganic & Medicinal Chemistry Letters, 2009
A novel class of CGRP receptor antagonists was rationally designed by modifying a highly potent, ... more A novel class of CGRP receptor antagonists was rationally designed by modifying a highly potent, but structurally complex, CGRP receptor antagonist. Initial modifications focused on simplified structures, with increased flexibility. Subsequent to the preparation of a less-potent but more flexible lead, classic medicinal chemistry methods were applied to restore high affinity (compound 22, CGRP K i = 0.035 nM) while maintaining structural diversity relative to the lead. Good selectivity against the closely related adrenomedullin-2 receptor was also achieved.
Bioorganic & Medicinal Chemistry Letters, 2010
A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint... more A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K i = 23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K i = 0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species.
Bioorganic & Medicinal Chemistry Letters, 2009
A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailab... more A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species.
ACS Medicinal Chemistry Letters, 2010
Incorporation of polar functionality into a series of highly potent calcitonin gene-related pepti... more Incorporation of polar functionality into a series of highly potent calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort to improve pharmacokinetics. This strategy identified piperazinone analogues that possessed improved solubility at acidic pH and increased oral bioavailability in monkeys. Further optimization led to the discovery of the clinical candidate 2-[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) (4), the most potent orally active CGRP receptor antagonist described to date.
ACS Medicinal Chemistry Letters, 2013
Rational modification of the potent calcitonin gene-related peptide (CGRP) receptor antagonist MK... more Rational modification of the potent calcitonin gene-related peptide (CGRP) receptor antagonist MK-3207 led to a series of analogues with enhanced CNS penetrance and a convenient chemical handle for introduction of a radiolabel. A number of (11)C-tracers were synthesized and evaluated in vivo, leading to the identification of [(11)C]8 ([(11)C]MK-4232), the first positron emission tomography tracer for the CGRP receptor.
The 6-oxopurine phosphoribosyltransferase (HPRT, EC 2.4.2.8) from the hyperthermophile Pyrococcus... more The 6-oxopurine phosphoribosyltransferase (HPRT, EC 2.4.2.8) from the hyperthermophile Pyrococcus horikoshii was expressed in Escherichia coli and purified. Steady-state kinetic studies indicated that the enzyme is able to use hypoxanthine, guanine and xanthine. The first two substrates showed similar catalytic efficiencies, and xanthine presented a much lower value (around 20 times lower), but the catalytic constant was comparable to that
Bioorganic & Medicinal Chemistry Letters, 2015
In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaff... more In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67nM), and selective compound (hERG IC50=19μM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold).
Journal of Medicinal Chemistry, 2001
The synthesis, structure-activity relationships, and biological properties of a novel series of i... more The synthesis, structure-activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with excellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of cell potency to intrinsic potency, compared with other known FTIs. It exhibited excellent potency against a range of tumor cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.
Journal of Medicinal Chemistry, 2002
A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synth... more A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.
Bioorganic & Medicinal Chemistry Letters, 2009
Rational modification of a previously identified spirohydantoin lead structure has identified a s... more Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K i = 40 pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.
Bioorganic & Medicinal Chemistry Letters, 2001
A series of amino acid-based linkers was used to investigate the effects of various substituents ... more A series of amino acid-based linkers was used to investigate the effects of various substituents upon the potency, pharmacokinetic properties, and conformation of macrocyclic farnesyl-protein transferase inhibitors (FTIs). As a result of the studies described herein, highly potent FTIs with improved pharmacokinetic profiles have been identified.
Bioorganic & Medicinal Chemistry Letters, 2006
Bioorganic & Medicinal Chemistry Letters, 2009
A novel class of CGRP receptor antagonists was rationally designed by modifying a highly potent, ... more A novel class of CGRP receptor antagonists was rationally designed by modifying a highly potent, but structurally complex, CGRP receptor antagonist. Initial modifications focused on simplified structures, with increased flexibility. Subsequent to the preparation of a less-potent but more flexible lead, classic medicinal chemistry methods were applied to restore high affinity (compound 22, CGRP K i = 0.035 nM) while maintaining structural diversity relative to the lead. Good selectivity against the closely related adrenomedullin-2 receptor was also achieved.
Bioorganic & Medicinal Chemistry Letters, 2010
A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint... more A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K i = 23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K i = 0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species.
Bioorganic & Medicinal Chemistry Letters, 2009
A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailab... more A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species.
ACS Medicinal Chemistry Letters, 2010
Incorporation of polar functionality into a series of highly potent calcitonin gene-related pepti... more Incorporation of polar functionality into a series of highly potent calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort to improve pharmacokinetics. This strategy identified piperazinone analogues that possessed improved solubility at acidic pH and increased oral bioavailability in monkeys. Further optimization led to the discovery of the clinical candidate 2-[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) (4), the most potent orally active CGRP receptor antagonist described to date.
ACS Medicinal Chemistry Letters, 2013
Rational modification of the potent calcitonin gene-related peptide (CGRP) receptor antagonist MK... more Rational modification of the potent calcitonin gene-related peptide (CGRP) receptor antagonist MK-3207 led to a series of analogues with enhanced CNS penetrance and a convenient chemical handle for introduction of a radiolabel. A number of (11)C-tracers were synthesized and evaluated in vivo, leading to the identification of [(11)C]8 ([(11)C]MK-4232), the first positron emission tomography tracer for the CGRP receptor.
The 6-oxopurine phosphoribosyltransferase (HPRT, EC 2.4.2.8) from the hyperthermophile Pyrococcus... more The 6-oxopurine phosphoribosyltransferase (HPRT, EC 2.4.2.8) from the hyperthermophile Pyrococcus horikoshii was expressed in Escherichia coli and purified. Steady-state kinetic studies indicated that the enzyme is able to use hypoxanthine, guanine and xanthine. The first two substrates showed similar catalytic efficiencies, and xanthine presented a much lower value (around 20 times lower), but the catalytic constant was comparable to that