George Njoroge - Academia.edu (original) (raw)
Papers by George Njoroge
Journal of Biological Chemistry, 1989
Recent work from this laboratory revealed that glucose-derived pyrroles can form with model amine... more Recent work from this laboratory revealed that glucose-derived pyrroles can form with model amines under physiological conditions (Niroge, F. G., Sayre, L. M., and Monnier, V. M. (1987) Carbohydr. Res. 167, 2 1 1-220). The major extractable product, 5-hydroxymethyl-1-alkylpyrrole-2-carbaldehyde (named by us pyrraline) was labile to acid hydrolysis. To allow its detection in proteins undergoing advanced glycosylation, an enzyme-linked immunosorbent assay was developed. An immunogen consisting of c-caproyl pyrraline (hapten) was linked onto poly-L-lysine (1 14:l) and used to raise polyclonal antibodies in the rabbit. High antibody titers were obtained 16 weeks after immunization. The antibody cross-reacted with butyl pyrraline (88%), propyl pyrraline (8%), lysyl pyrraline (2%), and neopentyl pyrraline (1.3%). A time-related increase in pyrraline immunoreactivity was observed in bovine serum albumin incubated with glucose (1000 mM), glycated lysine (50 mM), and 3-deoxyglucosone (50 mM) which reached 25, 300, and 350 pmol/mg, respectively, after 30 days. Mean level of protein pyrraline immunoreactivity were 27.0 f 7.2 and 43.3 f 11.7 pmol/mg in serum albumin from control and diabetic subjects, respectively (p c 0.001). The pathobiological relevance of pyrraline may relate to its reported antiproteolytic and mutagenic properties. In addition, glucose-derived pyrroles may play a role in diabetic neuropathy in analogy to pyrroles formed during hexane-induced neuropathy. Glucose can react nonenzymatically with free amino groups on proteins to form a Schiff base adduct which is then stabilized by an Amadori rearrangement. This reaction represents the early step of the so-called Maillard reaction which has been known for decades in food science (1, 2). In the advanced Maillard reaction, the Amadori product is degraded into deoxyglucosones which react again with free amino groups to form chromophores, fluorophores, and protein cross-links (1, 3). This latter process is also referred to as nonenzymatic browning or advanced glycosylation (1, 4). Nonenzymatic browning was hypothesized to contribute to
Bioorganic & medicinal chemistry letters, Jul 30, 2016
HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays... more HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein, we describe research efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A inhibitors such as 24, 39, 40, 43, and 44 which have pan-genotype activity and are orally bioavailable in the rat.
The Journal of Organic Chemistry, 2000
Journal of Medicinal Chemistry, 1998
We previously reported compound 1 as a potent farnesyl protein transferase (FPT) inhibitor that e... more We previously reported compound 1 as a potent farnesyl protein transferase (FPT) inhibitor that exhibited reasonable pharmacokinetic stability and showed moderate in vivo activity against a variety of tumor cell lines. The analogous C-11 single compound, pyridylacetamide 2, was found to be more potent than 1 in FPT inhibition. Further studies showed that modification of the ethano bridge of the tricyclic ring system by conversion into a double bond with concomitant introduction of a single bond at C-11 piperidine resulted in compound 3 that had superior FPT activity and pharmacokinetic stability. Compound 4, a 5-bromo-substituted analogue of 3, showed improved FPT activity, had good cellular activity, and demonstrated a remarkably improved pharmacokinetic profile with AUC of 84.9 and t1/2 of 82 min. Compound4 inhibited the growth of solid tumor in DLD-1 model by 70% at 50 mpk and 52% at 10 mpk.
Journal of Medicinal Chemistry, 1997
Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive ... more Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure-activity relationship (SAR) study of compounds arising from substitution at the 3-position of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.
Journal of Chemical Theory and Computation, 2006
The effect of the resistance mutations A156T, D168V, and D168Q in HCV protease on the binding of ... more The effect of the resistance mutations A156T, D168V, and D168Q in HCV protease on the binding of SCH 6, SCH 503034, VX-950, BILN-2061, and compound 1 was evaluated using the free energy perturbation (FEP) approach. All the inhibitors are highly potent against the wild-type enzyme, but their activity was affected differently by the mutants. A156T reduced the activity of SCH 503034, BILN-2061, and VX950 drastically (200-1000-fold) but that of SCH 6 only moderately (27-fold). SCH 503034, SCH 6, and VX-950 were not affected by either mutation D168V or D168Q, but these mutations conferred a high level of resistance to BILN-2061. Comparison of BILN-2061 with its acyclic analogue compound 1 emphasized the importance of inhibitor flexibility in overcoming drug resistance arising from the D168Q mutation. The results from FEP calculations compared well with experimental binding potencies within an error of <1 kcal/mol. Structural analysis was carried out to relate the resistance profiles to the atomic changes in the mutants.
Journal of Biological Chemistry, 1995
Bioorganic & Medicinal Chemistry Letters, 1996
... F. George Njoroge * , Bancha Vibulbhan, Carmen S. Alvarez, W. Robert Bishop, Joanne Petrin, R... more ... F. George Njoroge * , Bancha Vibulbhan, Carmen S. Alvarez, W. Robert Bishop, Joanne Petrin, Ronald J. Doll, V. Girijavallabhan and Ashit K ... 1996, 6, 2963 Jeffrey D. Winkler* and Paul H. Axelsen,* Departments of Chemistry and Pharmacology, The University of Pennsylvania ...
Bioorganic & Medicinal Chemistry Letters, 2004
Fused pyridine derivatives R 0450 Bridgehead Modification of Trihalocycloheptabenzopyridine Lead ... more Fused pyridine derivatives R 0450 Bridgehead Modification of Trihalocycloheptabenzopyridine Lead to a Potent Farnesyl Protein Transferase Inhibitor with Improved Oral Metabolic Stability.-The core structure of the antitumor agent SARASAR (SCH66336) (I) is modified. The (S)-isomers (IIb) and (IIc) are particularly active with IC50 values in the picomolar range.
Bioorganic & Medicinal Chemistry Letters, 2010
The discovery of Clinked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This ... more The discovery of Clinked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This novel class of compounds are sub nM FPT enzyme inhibitors with potent cellular inhibitory activities. This series also has reduced hERG activity versus previous N-linked imidazole series. X-ray of compound 10a bound to FTase revealed strong interaction between bridgehead imidazole 3N with catalytic zinc atom.
Bioorganic & Medicinal Chemistry, 1997
A comprehensive structure-activity relationship (SAR) study of novel tricyclic amides has been un... more A comprehensive structure-activity relationship (SAR) study of novel tricyclic amides has been undertaken. The discovery of compounds that are potent FPT inhibitors in the nanomolar range has been achieved. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit farnesyl protein transferase (FPT) and not geranylgeranyl protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in Cos monkey kidney cells.
Antimicrobial Agents and Chemotherapy, 2006
ABSTRACTCleavage of the hepatitis C virus (HCV) polyprotein by the viral NS3 protease releases fu... more ABSTRACTCleavage of the hepatitis C virus (HCV) polyprotein by the viral NS3 protease releases functional viral proteins essential for viral replication. Recent studies by Foy and coworkers strongly suggest that NS3-mediated cleavage of host factors may abrogate cellular response to alpha interferon (IFN-α) (E. Foy, K. Li, R. Sumpter, Jr., Y.-M. Loo, C. L. Johnson, C. Wang, P. M. Fish, M. Yoneyama, T. Fujita, S. M. Lemon, and M. Gale, Jr., Proc. Natl. Acad. Sci. USA102:2986-2991, 2005, and E. Foy, K. Li, C. Wang, R. Sumpter, Jr., M. Ikeda, S. M. Lemon, and M. Gale, Jr., Science300:1145-1148, 2003). Blockage of NS3 protease activity therefore is expected to inhibit HCV replication by both direct suppression of viral protein production as well as by restoring host responsiveness to IFN. Using structure-assisted design, a ketoamide inhibitor, SCH 503034, was generated which demonstrated potent (overall inhibition constant, 14 nM) time-dependent inhibition of the NS3 protease in cell-fr...
Journal of Medicinal Chemistry, 1999
Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with n... more Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with novel tricyclic inhibitors provide insights into the observed SAR for this unique class of nonpeptidic FPT inhibitors. The crystallographic structures reveal a binding pattern conserved across the mono-, di-, and trihalogen series. In the complexes, the tricycle spans the FPT active site cavity and interacts with both protein atoms and the isoprenoid portion of bound farnesyl diphosphate. An amide carbonyl, common to the tricyclic compounds described here, participates in a water-mediated hydrogen bond to the protein backbone. Ten high-resolution crystal structures of inhibitors complexed with FPT are reported. Included are crystallographic data for FPT complexed with SCH 66336, a compound currently undergoing clinical trials as an anticancer agent (SCH 66336, 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxamide). Thermodynamic binding parameters show favorable enthalpies of complex formation and small net entropic contributions as observed for 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-11H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]pyridine N-oxide where ∆H°b ind)-12.5 kcal/mol and T∆S°b ind)-1.5 kcal/mol.
Letters in Drug Design & Discovery, 2009
ABSTRACT Boceprevir is a novel hepatitis C virus (HCV) protease inhibitor undergoing clinical inv... more ABSTRACT Boceprevir is a novel hepatitis C virus (HCV) protease inhibitor undergoing clinical investigation for use in the treatment of human HCV infection. Preclinical in vivo pharmacokinetic studies have been performed in rat, dog, and/or monkey after single administration by oral and intravenous routes for about one thousand compounds prior to the selection of boceprevir as the development candidate. In vitro pharmacokinetic assessments of metabolic stability, cell permeability, and plasma protein binding have been performed. The compound has physicochemical properties (molecular weight of 519.7 and moderate lipophilicity and H-bonding functionalities) that are borderline for good pharmacokinetic behavior. Absorption in animals ranges from 12 to 37%, indicating incomplete absorption. Based on in vitro permeability studies in Caco-2 cells, boceprevir appears to be an efflux substrate displaying a saturable efflux profile at high dosing concentrations and a reversible efflux profile in the presence of P-glycoprotein (P-gp) inhibitors. Boceprevir displayed a rather high liver/plasma average ratio of 30 in rats, indicating good uptake by the target tissue. The rat liver/plasma ratio of boceprevir appeared to be higher than those for compounds that are under clinical evaluation. Based on the preclinical pharmacokinetic data, boceprevir appears to have limited absorption, but reasonable liver distribution which is a primary factor for selecting boceprevir as a development candidate. Recent clinical proof-of-concept study confirmed that boceprevir is efficacious in reducing the viral load in patients.
ACS Medicinal Chemistry Letters, 2010
Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laborator... more Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (∼10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.
Journal of Biological Chemistry, 1989
Recent work from this laboratory revealed that glucose-derived pyrroles can form with model amine... more Recent work from this laboratory revealed that glucose-derived pyrroles can form with model amines under physiological conditions (Niroge, F. G., Sayre, L. M., and Monnier, V. M. (1987) Carbohydr. Res. 167, 2 1 1-220). The major extractable product, 5-hydroxymethyl-1-alkylpyrrole-2-carbaldehyde (named by us pyrraline) was labile to acid hydrolysis. To allow its detection in proteins undergoing advanced glycosylation, an enzyme-linked immunosorbent assay was developed. An immunogen consisting of c-caproyl pyrraline (hapten) was linked onto poly-L-lysine (1 14:l) and used to raise polyclonal antibodies in the rabbit. High antibody titers were obtained 16 weeks after immunization. The antibody cross-reacted with butyl pyrraline (88%), propyl pyrraline (8%), lysyl pyrraline (2%), and neopentyl pyrraline (1.3%). A time-related increase in pyrraline immunoreactivity was observed in bovine serum albumin incubated with glucose (1000 mM), glycated lysine (50 mM), and 3-deoxyglucosone (50 mM) which reached 25, 300, and 350 pmol/mg, respectively, after 30 days. Mean level of protein pyrraline immunoreactivity were 27.0 f 7.2 and 43.3 f 11.7 pmol/mg in serum albumin from control and diabetic subjects, respectively (p c 0.001). The pathobiological relevance of pyrraline may relate to its reported antiproteolytic and mutagenic properties. In addition, glucose-derived pyrroles may play a role in diabetic neuropathy in analogy to pyrroles formed during hexane-induced neuropathy. Glucose can react nonenzymatically with free amino groups on proteins to form a Schiff base adduct which is then stabilized by an Amadori rearrangement. This reaction represents the early step of the so-called Maillard reaction which has been known for decades in food science (1, 2). In the advanced Maillard reaction, the Amadori product is degraded into deoxyglucosones which react again with free amino groups to form chromophores, fluorophores, and protein cross-links (1, 3). This latter process is also referred to as nonenzymatic browning or advanced glycosylation (1, 4). Nonenzymatic browning was hypothesized to contribute to
Bioorganic & medicinal chemistry letters, Jul 30, 2016
HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays... more HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein, we describe research efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A inhibitors such as 24, 39, 40, 43, and 44 which have pan-genotype activity and are orally bioavailable in the rat.
The Journal of Organic Chemistry, 2000
Journal of Medicinal Chemistry, 1998
We previously reported compound 1 as a potent farnesyl protein transferase (FPT) inhibitor that e... more We previously reported compound 1 as a potent farnesyl protein transferase (FPT) inhibitor that exhibited reasonable pharmacokinetic stability and showed moderate in vivo activity against a variety of tumor cell lines. The analogous C-11 single compound, pyridylacetamide 2, was found to be more potent than 1 in FPT inhibition. Further studies showed that modification of the ethano bridge of the tricyclic ring system by conversion into a double bond with concomitant introduction of a single bond at C-11 piperidine resulted in compound 3 that had superior FPT activity and pharmacokinetic stability. Compound 4, a 5-bromo-substituted analogue of 3, showed improved FPT activity, had good cellular activity, and demonstrated a remarkably improved pharmacokinetic profile with AUC of 84.9 and t1/2 of 82 min. Compound4 inhibited the growth of solid tumor in DLD-1 model by 70% at 50 mpk and 52% at 10 mpk.
Journal of Medicinal Chemistry, 1997
Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive ... more Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure-activity relationship (SAR) study of compounds arising from substitution at the 3-position of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.
Journal of Chemical Theory and Computation, 2006
The effect of the resistance mutations A156T, D168V, and D168Q in HCV protease on the binding of ... more The effect of the resistance mutations A156T, D168V, and D168Q in HCV protease on the binding of SCH 6, SCH 503034, VX-950, BILN-2061, and compound 1 was evaluated using the free energy perturbation (FEP) approach. All the inhibitors are highly potent against the wild-type enzyme, but their activity was affected differently by the mutants. A156T reduced the activity of SCH 503034, BILN-2061, and VX950 drastically (200-1000-fold) but that of SCH 6 only moderately (27-fold). SCH 503034, SCH 6, and VX-950 were not affected by either mutation D168V or D168Q, but these mutations conferred a high level of resistance to BILN-2061. Comparison of BILN-2061 with its acyclic analogue compound 1 emphasized the importance of inhibitor flexibility in overcoming drug resistance arising from the D168Q mutation. The results from FEP calculations compared well with experimental binding potencies within an error of <1 kcal/mol. Structural analysis was carried out to relate the resistance profiles to the atomic changes in the mutants.
Journal of Biological Chemistry, 1995
Bioorganic & Medicinal Chemistry Letters, 1996
... F. George Njoroge * , Bancha Vibulbhan, Carmen S. Alvarez, W. Robert Bishop, Joanne Petrin, R... more ... F. George Njoroge * , Bancha Vibulbhan, Carmen S. Alvarez, W. Robert Bishop, Joanne Petrin, Ronald J. Doll, V. Girijavallabhan and Ashit K ... 1996, 6, 2963 Jeffrey D. Winkler* and Paul H. Axelsen,* Departments of Chemistry and Pharmacology, The University of Pennsylvania ...
Bioorganic & Medicinal Chemistry Letters, 2004
Fused pyridine derivatives R 0450 Bridgehead Modification of Trihalocycloheptabenzopyridine Lead ... more Fused pyridine derivatives R 0450 Bridgehead Modification of Trihalocycloheptabenzopyridine Lead to a Potent Farnesyl Protein Transferase Inhibitor with Improved Oral Metabolic Stability.-The core structure of the antitumor agent SARASAR (SCH66336) (I) is modified. The (S)-isomers (IIb) and (IIc) are particularly active with IC50 values in the picomolar range.
Bioorganic & Medicinal Chemistry Letters, 2010
The discovery of Clinked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This ... more The discovery of Clinked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This novel class of compounds are sub nM FPT enzyme inhibitors with potent cellular inhibitory activities. This series also has reduced hERG activity versus previous N-linked imidazole series. X-ray of compound 10a bound to FTase revealed strong interaction between bridgehead imidazole 3N with catalytic zinc atom.
Bioorganic & Medicinal Chemistry, 1997
A comprehensive structure-activity relationship (SAR) study of novel tricyclic amides has been un... more A comprehensive structure-activity relationship (SAR) study of novel tricyclic amides has been undertaken. The discovery of compounds that are potent FPT inhibitors in the nanomolar range has been achieved. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit farnesyl protein transferase (FPT) and not geranylgeranyl protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in Cos monkey kidney cells.
Antimicrobial Agents and Chemotherapy, 2006
ABSTRACTCleavage of the hepatitis C virus (HCV) polyprotein by the viral NS3 protease releases fu... more ABSTRACTCleavage of the hepatitis C virus (HCV) polyprotein by the viral NS3 protease releases functional viral proteins essential for viral replication. Recent studies by Foy and coworkers strongly suggest that NS3-mediated cleavage of host factors may abrogate cellular response to alpha interferon (IFN-α) (E. Foy, K. Li, R. Sumpter, Jr., Y.-M. Loo, C. L. Johnson, C. Wang, P. M. Fish, M. Yoneyama, T. Fujita, S. M. Lemon, and M. Gale, Jr., Proc. Natl. Acad. Sci. USA102:2986-2991, 2005, and E. Foy, K. Li, C. Wang, R. Sumpter, Jr., M. Ikeda, S. M. Lemon, and M. Gale, Jr., Science300:1145-1148, 2003). Blockage of NS3 protease activity therefore is expected to inhibit HCV replication by both direct suppression of viral protein production as well as by restoring host responsiveness to IFN. Using structure-assisted design, a ketoamide inhibitor, SCH 503034, was generated which demonstrated potent (overall inhibition constant, 14 nM) time-dependent inhibition of the NS3 protease in cell-fr...
Journal of Medicinal Chemistry, 1999
Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with n... more Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with novel tricyclic inhibitors provide insights into the observed SAR for this unique class of nonpeptidic FPT inhibitors. The crystallographic structures reveal a binding pattern conserved across the mono-, di-, and trihalogen series. In the complexes, the tricycle spans the FPT active site cavity and interacts with both protein atoms and the isoprenoid portion of bound farnesyl diphosphate. An amide carbonyl, common to the tricyclic compounds described here, participates in a water-mediated hydrogen bond to the protein backbone. Ten high-resolution crystal structures of inhibitors complexed with FPT are reported. Included are crystallographic data for FPT complexed with SCH 66336, a compound currently undergoing clinical trials as an anticancer agent (SCH 66336, 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxamide). Thermodynamic binding parameters show favorable enthalpies of complex formation and small net entropic contributions as observed for 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-11H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]pyridine N-oxide where ∆H°b ind)-12.5 kcal/mol and T∆S°b ind)-1.5 kcal/mol.
Letters in Drug Design & Discovery, 2009
ABSTRACT Boceprevir is a novel hepatitis C virus (HCV) protease inhibitor undergoing clinical inv... more ABSTRACT Boceprevir is a novel hepatitis C virus (HCV) protease inhibitor undergoing clinical investigation for use in the treatment of human HCV infection. Preclinical in vivo pharmacokinetic studies have been performed in rat, dog, and/or monkey after single administration by oral and intravenous routes for about one thousand compounds prior to the selection of boceprevir as the development candidate. In vitro pharmacokinetic assessments of metabolic stability, cell permeability, and plasma protein binding have been performed. The compound has physicochemical properties (molecular weight of 519.7 and moderate lipophilicity and H-bonding functionalities) that are borderline for good pharmacokinetic behavior. Absorption in animals ranges from 12 to 37%, indicating incomplete absorption. Based on in vitro permeability studies in Caco-2 cells, boceprevir appears to be an efflux substrate displaying a saturable efflux profile at high dosing concentrations and a reversible efflux profile in the presence of P-glycoprotein (P-gp) inhibitors. Boceprevir displayed a rather high liver/plasma average ratio of 30 in rats, indicating good uptake by the target tissue. The rat liver/plasma ratio of boceprevir appeared to be higher than those for compounds that are under clinical evaluation. Based on the preclinical pharmacokinetic data, boceprevir appears to have limited absorption, but reasonable liver distribution which is a primary factor for selecting boceprevir as a development candidate. Recent clinical proof-of-concept study confirmed that boceprevir is efficacious in reducing the viral load in patients.
ACS Medicinal Chemistry Letters, 2010
Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laborator... more Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (∼10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.