A para substitution pattern of the phenyl ring is a characteristic feature of the first reported selective AT(2) receptor agonist M024/C21 (1) and all the nonpeptidic AT(2) receptor agonists described so far. Two series of compounds structurally related to 1 but with a meta substitution pattern have now been synthesized and biologically evaluated for their affinity to the AT(1) and AT(2) receptors. A high AT(2)/AT(1) receptor selectivity was obtained with all 41 compounds synthesized, and the majority exhibited K(i) ranging from 2 to 100 nM. Five compounds were evaluated for their functional activity at the AT(2) receptor, applying a neurite outgrowth assay in NG108-15 cells. Notably, four of the five compounds, with representatives from both series, acted as potent AT(2) receptor antagonists. These compounds were found to be considerably more effective than PD 123,319, the standard AT(2) receptor antagonist used in most laboratories. No AT(2) receptor antagonists were previously reported among the derivatives with a para substitution pattern. Hence, by a minor modification of the agonist 1 it could be transformed into the antagonist, compound 38. These compounds should serve as valuable tools in the assessment of the role of the AT(2) receptor in more complex physiological models.
In an effort to identify a new class of druglike HIV-1
protease
inhibitors, four different stereopure β-hydroxy γ-lactam-containing
inhibitors have been synthesized, biologically evaluated, and cocrystallized.
The impact of the tether length of the central spacer (two or three
carbons) was also investigated. A compound with a shorter tether and
(3R,4S) absolute configuration exhibited
high activity with a Ki of 2.1 nM and
an EC50 of 0.64 μM. Further optimization by decoration
of the P1′ side chain furnished an even more potent HIV-1 protease
inhibitor (Ki = 0.8 nM, EC50 = 0.04 μM). According to X-ray analysis, the new class of
inhibitors did not fully succeed in forming two symmetric hydrogen
bonds to the catalytic aspartates. The crystal structures of the complexes
further explain the difference in potency between the shorter inhibitors
(two-carbon spacer) and the longer inhibitors (three-carbon spacer).
To study P1-P3 macrocyclizations of previously reported tertiary-alcohol-comprising HIV-1 protease inhibitors (PIs), three new 14- and 15-member macrocyclic PIs were designed, synthesized by ring-closing metathesis, and evaluated alongside with 10 novel linear PIs. Cocrystallized complexes of the macrocyclic PIs and the HIV-1 protease are presented, analyzed, and discussed. The macrocyclic structures exhibited higher activities than the linear precursors with Ki and EC50 values down to 3.1 nM and 0.37 μM, respectively.
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