3 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
The Discovery of 3‑((4-Chloro-3-methoxyphenyl)amino)-1-((3<i>R</i>,4<i>S</i>)‑4-cyanotetrahydro‑2<i>H</i>‑pyran-3-yl)‑1<i>H</i>‑pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties
The
discovery of a potent selective low dose Janus kinase 1 (JAK1)
inhibitor suitable for clinical evaluation is described. As part of
an overall goal to minimize dose, we pursued a medicinal chemistry
strategy focused on optimization of key parameters that influence
dose size, including lowering human Cl<sub>int</sub> and increasing
intrinsic potency, bioavailability, and solubility. To impact these
multiple parameters simultaneously, we used lipophilic ligand efficiency
as a key metric to track changes in the physicochemical properties
of our analogs, which led to improvements in overall compound quality.
In parallel, structural information guided advancements in JAK1 selectivity
by informing on new vector space, which enabled the discovery of a
unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939).
This difference was exploited to consistently produce analogs with
the best balance of JAK1 selectivity, efficacy, and projected human
dose, ultimately culminating in the discovery of compound <b>28</b>