4 research outputs found
Design, Synthesis, Structure–Function Relationship, Bioconversion, and Pharmacokinetic Evaluation of Ertapenem Prodrugs
Described here are synthesis and
biological evaluations of diversified
groups of over 57 ertapenem prodrugs which include alkyl, methylenedioxy,
carbonate, cyclic carbonate, carbamate esters, and esters containing
active transport groups (e.g., carboxyl, amino acid, fatty acids,
cholesterol) and macrocyclic lactones linking the two carboxyl groups.
Many of the prodrugs were rapidly hydrolyzed in rat plasma but not
in human plasma and were stable in simulated gastrointestinal fluid.
The diethyl ester prodrug showed the best total absorption (>30%)
by intredeudenal dosing in dogs, which could potentially be improved
by formulation development. However, its slow rate of the hydrolysis
to ertapenem also led to the presence of large amounts of circulating
monoester metabolites, which pose significant development challenges.
This study also suggests that the size of susbtituents at C-2 of carbapenem
(e.g., benzoic acid of ertapenem) has significant impact on the absorption
and the hydrolysis of the prodrugs
Design, Synthesis, and Evaluation of Prodrugs of Ertapenem
Carbapenems are intravenous lifesaving
hospital antibiotics. Once
patients leave the hospital, they are sent home with antibiotics other
than carbapenems since they cannot be administered orally due to lack
of oral absorption primarily because of very highly polarity. A prodrug
approach is a bona fide strategy to improve oral absorption of compounds.
Design and synthesis, in vitro and in vivo evaluation of diversified
prodrugs of ertapenem, one of the only once daily dosed carbapenems
is described. Many of the prodrugs prepared for evaluation are rapidly
hydrolyzed in rat plasma. Only bis-(5-methyl-2-oxo-1,3-dioxol-4-yl)Âmethyl
(medoxomil) ester prodrug was rapidly hydrolyzed in most of the plasmas
including rat, human, dog, and monkey. Although the rate of conversion
of ertapenem diethyl ester prodrug (<b>6</b>) was slow in in
vitro plasma hydrolysis, it showed the best in vivo pharmacokinetic
profile in dog by an intraduodenal dosing giving >31% total oral
absorption
Discovery of Chromane Propionic Acid Analogues as Selective Agonists of GPR120 with <i>in Vivo</i> Activity in Rodents
GPR120 (FFAR4) is
a fatty acid sensing G protein coupled receptor
(GPCR) that has been identified as a target for possible treatment
of type 2 diabetes. A selective activator of GPR120 containing a chromane
scaffold has been designed, synthesized, and evaluated <i>in
vivo</i>. Results of these efforts suggest that chromane propionic
acid <b>18</b> is a suitable tool molecule for further animal
studies. Compound <b>18</b> is selective over the closely related
target GPR40 (FFAR1), has a clean off-target profile, demonstrates
suitable pharmacokinetic properties, and has been evaluated in wild-type/knockout
GPR120 mouse oGTT studies
Design, Synthesis, and Evaluation of Novel and Selective G‑protein Coupled Receptor 120 (GPR120) Spirocyclic Agonists
Type 2 diabetes mellitus
(T2DM) is an ever increasing worldwide
epidemic, and the identification of safe and effective insulin sensitizers,
absent of weight gain, has been a long-standing goal of diabetes research.
G-protein coupled receptor 120 (GPR120) has recently emerged as a
potential therapeutic target for treating T2DM. Natural occurring,
and more recently, synthetic agonists have been associated with insulin
sensitizing, anti-inflammatory, and fat metabolism effects. Herein
we describe the design, synthesis, and evaluation of a novel spirocyclic
GPR120 agonist series, which culminated in the discovery of potent
and selective agonist <b>14</b>. Furthermore, compound <b>14</b> was evaluated <i>in vivo</i> and demonstrated
acute glucose lowering in an oral glucose tolerance test (oGTT), as
well as improvements in homeostatic measurement assessment of insulin
resistance (HOMA-IR; a surrogate marker for insulin sensitization)
and an increase in glucose infusion rate (GIR) during a hyperinsulinemic
euglycemic clamp in diet-induced obese (DIO) mice