Conduritol B epoxide (CBE, ot,-1,2-anhydro-myu-inositol, (8)) is an in-activating inhibitor of se... more Conduritol B epoxide (CBE, ot,-1,2-anhydro-myu-inositol, (8)) is an in-activating inhibitor of several D-glucosidases, particularly the mammalian enzyme which cleaves glucosylceramide. This enzyme is defective in the human genetic disorder Gaucher disease, and the ready availability of the inhibitor would enable investigators to study the disorder in animal models. The synthetic route to 8, based on the procedures of Angyal et al. ‘, Nakajima et aL2, Nagabhushan”. Leglet’, and Radin and Vunnam”, utilized the readily available myo-inositol (1) as starting material. The need for larger amounts and less variable yields led us to study the steps in greater depth, by use of t.1.c. and g.1.c. in time studies. A somewhat improved, faster method is described, in which only two recrystallization steps are required. A design for a large Abderhalden drying pistol is described. The first step, glycol protection with cyclohexanone, utilized p-toluene-sulfonic acid as catalyst and benzene as the ...
A major antimicrobial resistance mechanism in Gramnegative bacteria is the production of β-lactam... more A major antimicrobial resistance mechanism in Gramnegative bacteria is the production of β-lactamase enzymes. The increasing emergence of β-lactamase-producing multi-drug-resistant "superbugs" has resulted in increases in costly hospital Emergency Department (ED) visits and hospitalizations due to the requirement for parenteral antibiotic therapy for infections caused by these difficult-totreat bacteria. To address the lack of outpatient treatment, we initiated an iterative program combining medicinal chemistry, biochemical testing, microbiological profiling, and evaluation of oral pharmacokinetics. Lead optimization focusing on multiple smaller, more lipophilic active compounds, followed by an exploration of oral bioavailability of a variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236 etzadroxil), the prodrug of the boronic acid-containing β-lactamase inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum β-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.
X series of nonpcptidic human rcnin inhibitors with a 4-mcthoxymcthoxypipcridinylamide at the P4 ... more X series of nonpcptidic human rcnin inhibitors with a 4-mcthoxymcthoxypipcridinylamide at the P4 position of the n~oIcculc exhibited slow tight binding IO the cnzymc. Rcplaczmcnt of the mcthoxymcthoxy moiety on the pipcridinc ring with H. OH, mcthoxycthyl. propyloxy or rr-butyl climinatcd ihc &l&t. The inhibition was partially rcvcrscd by prolonged dialysis at 4°C. arguing against formation of a covalent bond in the tightcncd complex.
A compound selected from Formula ** ** Formula and salts thereof, wherein: L is O, S, C (> = O... more A compound selected from Formula ** ** Formula and salts thereof, wherein: L is O, S, C (> = O) or CHR14; Y is N or CR4; Z is N or CR3, wherein at least one of G or Z is not N; G is N or CR11; R1 is a heteroaryl ring represented by the formula ** ** Formula D1 is S, O or N; D2 is N or CR12; D3 is S, O or CR13; R2 is aryl, heteroaryl, saturated or partially unsaturated cycloalkyl, or saturated or partially unsaturated heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are monocyclic or bicyclic and are optionally substituted with one or more groups independently selected from C1-C6 alkyl, alkenyl C2-C6, C2-C6 alkynyl, C3-C6 saturated or partially unsaturated heterocyclyl C1-C6 saturated or partially unsaturated, aryl, heteroaryl, F, Cl, Br, I, CF3, CN, NO2, OR6, C (> = O) R6, C (> = O) OR6, OC (> = O) R6, O (CH2) nC (> = O) OR6, O (CH2) nC (> = O) NR6R7, C (> = O ) NR6R7, NR6R7, NR 6 C (> = O) R7, SR6, S (O) R6 and S (O) 2R6, and wherein ...
Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the ... more Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure−activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC 50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.
Conduritol B epoxide (CBE, ot,-1,2-anhydro-myu-inositol, (8)) is an in-activating inhibitor of se... more Conduritol B epoxide (CBE, ot,-1,2-anhydro-myu-inositol, (8)) is an in-activating inhibitor of several D-glucosidases, particularly the mammalian enzyme which cleaves glucosylceramide. This enzyme is defective in the human genetic disorder Gaucher disease, and the ready availability of the inhibitor would enable investigators to study the disorder in animal models. The synthetic route to 8, based on the procedures of Angyal et al. ‘, Nakajima et aL2, Nagabhushan”. Leglet’, and Radin and Vunnam”, utilized the readily available myo-inositol (1) as starting material. The need for larger amounts and less variable yields led us to study the steps in greater depth, by use of t.1.c. and g.1.c. in time studies. A somewhat improved, faster method is described, in which only two recrystallization steps are required. A design for a large Abderhalden drying pistol is described. The first step, glycol protection with cyclohexanone, utilized p-toluene-sulfonic acid as catalyst and benzene as the ...
A major antimicrobial resistance mechanism in Gramnegative bacteria is the production of β-lactam... more A major antimicrobial resistance mechanism in Gramnegative bacteria is the production of β-lactamase enzymes. The increasing emergence of β-lactamase-producing multi-drug-resistant "superbugs" has resulted in increases in costly hospital Emergency Department (ED) visits and hospitalizations due to the requirement for parenteral antibiotic therapy for infections caused by these difficult-totreat bacteria. To address the lack of outpatient treatment, we initiated an iterative program combining medicinal chemistry, biochemical testing, microbiological profiling, and evaluation of oral pharmacokinetics. Lead optimization focusing on multiple smaller, more lipophilic active compounds, followed by an exploration of oral bioavailability of a variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236 etzadroxil), the prodrug of the boronic acid-containing β-lactamase inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum β-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.
X series of nonpcptidic human rcnin inhibitors with a 4-mcthoxymcthoxypipcridinylamide at the P4 ... more X series of nonpcptidic human rcnin inhibitors with a 4-mcthoxymcthoxypipcridinylamide at the P4 position of the n~oIcculc exhibited slow tight binding IO the cnzymc. Rcplaczmcnt of the mcthoxymcthoxy moiety on the pipcridinc ring with H. OH, mcthoxycthyl. propyloxy or rr-butyl climinatcd ihc &l&t. The inhibition was partially rcvcrscd by prolonged dialysis at 4°C. arguing against formation of a covalent bond in the tightcncd complex.
A compound selected from Formula ** ** Formula and salts thereof, wherein: L is O, S, C (> = O... more A compound selected from Formula ** ** Formula and salts thereof, wherein: L is O, S, C (> = O) or CHR14; Y is N or CR4; Z is N or CR3, wherein at least one of G or Z is not N; G is N or CR11; R1 is a heteroaryl ring represented by the formula ** ** Formula D1 is S, O or N; D2 is N or CR12; D3 is S, O or CR13; R2 is aryl, heteroaryl, saturated or partially unsaturated cycloalkyl, or saturated or partially unsaturated heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl are monocyclic or bicyclic and are optionally substituted with one or more groups independently selected from C1-C6 alkyl, alkenyl C2-C6, C2-C6 alkynyl, C3-C6 saturated or partially unsaturated heterocyclyl C1-C6 saturated or partially unsaturated, aryl, heteroaryl, F, Cl, Br, I, CF3, CN, NO2, OR6, C (> = O) R6, C (> = O) OR6, OC (> = O) R6, O (CH2) nC (> = O) OR6, O (CH2) nC (> = O) NR6R7, C (> = O ) NR6R7, NR6R7, NR 6 C (> = O) R7, SR6, S (O) R6 and S (O) 2R6, and wherein ...
Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the ... more Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure−activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC 50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.
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Papers by Steven Boyd