Structure/Activity Relationship of Gemfibrozil (CI-719) and Related Compounds

Creger, Paul L.; Moersch, G. W.; Neuklis, W. A.

doi:10.1177/00359157760690s202

Cited by 8 publications

(3 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gemfibrozil (in Scheme ) belongs to the class of fibric acid derivative and is mainly used in the treatment of hyperlipidemia. , It was first synthesized in 1972 and screened out as a new lipid-lowering drug by Creger in 1976 and subsequently marketed in the form of gemfibrozil in 1982 . Clinic studies show that gemfibrozil can prevent cardiovascular events by increasing HDL cholesterol .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Pharmacokinetic Study of Three Gemfibrozil Salts: An Exploration of the Structure–Property Relationship

Yang

Ren

Song

et al. 2016

Crystal Growth & Design

View full text Add to dashboard Cite

Three salts, [H3N(CH2)2NH3)][gem]2 (1), [H3N(CH2)3NH3)][gem]2·2H2O (2), and [H3N(CH2)4NH3)][gem]2·2H2O (3) of the minimally soluble drug gmfibrozil (Hgem), used for the treatment of hyperlipidemia have been synthesized by using a series of diamine with different carbon chain lengths and characterized by single crystal/powder X-ray diffraction, Fourier transform infrared spectroscopy, and 1H nuclear magnetic resonance. In the three salts, two protons of two gmfibrozil molecules transfer to one diamine, and the resulting organic diammonium cation and gmfibrozil anion are assembled by hydrogen bond interactions into a two-dimensional layer. Although the apparent solubility of salts 1–3 is obviously improved compared to that of the original gemfibrozil, pharmacokinetic studies in rats indicate the enhancement of absorption is limited with the relative bioavailability of 104% for 1, 154% for 2, and 108% for 3. It is notable that the rapid dissolution behavior of salt 1–3 leads to the increase of maximal plasma concentration (C max) and the dramatic shortening of the time required to reach the C max. The investigation of the structure–property relationship shows that there is little correlation of solubility with the carbon chain length of cation which is different from previous observations, and we speculate that both electrostatic attraction and hydrogen bond interaction contribute to the solubility order (2 > 1 > 3) .

show abstract

Section: Introductionmentioning

confidence: 99%

Synthesis and Pharmacokinetic Study of Three Gemfibrozil Salts: An Exploration of the Structure–Property Relationship

Yang

Ren

Song

et al. 2016

Crystal Growth & Design

View full text Add to dashboard Cite

show abstract

“…Specifically, two molecular modifications were performed: (1) replacing the p -chloro group with a p -chlorobenzoyl group and (2) replacing the ethyl ester functionality with an isopropyl ester to provide 144 , which was introduced to the U.S. market in late 1970s to treat hyperlipidemia . Compound 145 , discovered in 1976, is another fibrate belonging to the phenoxy-α,α-dimethylpentanoic acid class …”

Section: Pharmacodynamics Contribution Of a Gem-dimethyl Groupmentioning

confidence: 93%

“…140 Compound 145, discovered in 1976, is another fibrate belonging to the phenoxy-α,α-dimethylpentanoic acid class. 141 In a related phenoxyacetic acid series of fibrates (compounds 146 and 147), Sierra and colleagues 142 reported that removal of the α-gem-dimethyl group (phenoxyisobutyric acid to phenoxyacetic acid) resulted in a 5-to 10-fold loss of affinity toward two PPAR subtypes (Figure 43). This effect was rationalized by Xray crystal structure studies on structurally related PPARα agonists, which suggested contribution of the α-gem-dimethyl moiety in facilitating adoption of a conformation wherein the carboxylate and phenyl ring assumed a bioactive global minimum gauche relationship, as highlighted in Figure 43.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry

Talele

2017

J. Med. Chem.

107

View full text Add to dashboard Cite

The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p K of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.

show abstract