Azole Endothelin Antagonists. 3. Using Δ log P as a Tool To Improve Absorption

Abstract

The oral absorption profile of a family of azole-based ET(A)-selective antagonists has been improved through a rational series of structural modifications which were suggested by analysis of the physicochemical parameter delta log P. Comparison of urea 2 with a series of well-absorbed compounds using delta log P analysis suggested that 2 has an excess capacity for forming hydrogen bonds with solvent. A series of urea modifications were explored as a means of reducing H-bonding capacity while maintaining affinity for the ET(A)-receptor. The correlation between delta log P values and absorption in an intraduodenal (id) bioavailability model was good; this strategy uncovered replacements for each of the urea NH groups which simultaneously improve both potency and drug absorption. A combination of these optimized modifications produces carbamate 16h, a highly-selective ET(A) antagonist with a potency/bioavailability profile consistent with an oral route of administration.

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…[209,217,247,399,400] The presence of IMHB has been shown to significantly alter molecular properties due to formation of various conformers that in turn influence solubility, permeability, PK/ PD processes, and protein binding affinity [207,210,401,402].…”

“…A hydrogen bond is strong enough to restrict rotation of fragments by forming most commonly [210,217,401,402] membered rings. Importantly, IMHBs are weak enough to allow these fragments to come apart and lose their orientational specificity in high dielectric media such as water.…”

“…LogP is one of the most widely used parameters in drug design and it has been considered for evaluation of IMHB [391,402,410]. It has been demonstrated using solvatochromic equations that the difference between logP values obtained in different biphasic systems (ΔlogP), for example octanol/water and alkane/water (ΔlogP oct-alk = logP octlogP alk ), is informative of IMHB when the solvents are very different from each other [356].…”

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

“…[1][2][3][4][5] The presence of IMHB has been shown to significantly alter molecular properties due to formation of various conformers that in turn influence solubility, permeability, PK/ PD processes, and protein binding affinity. [6][7][8][9] The IMHB as described by Desiraju 10 is an attractive interaction in which an electropositive hydrogen atom intercedes between two electronegative fragments of the same molecule and holds them together. A hydrogen bond is strong enough to restrict rotation of fragments by forming most commonly 5-8 membered rings.…”

Leveraging chromatography based physicochemical properties for efficient drug design

“…The use of Δlog P = log P alkane/water -log P octanol/water was first introduced by Seiler [40] and applied to improve absorption [41], as a guide in the design of novel brain-penetrating H2 antagonists [42], or as a measure of HBD acidity [43,44]. Hydrogen bonds characteristically feature binding energies and contact distances that can lead to large variations even for a single donor-acceptor pair [45].…”