Kinetic Models of Cyclosporin A in Polar and Apolar Environments Reveal Multiple Congruent Conformational States

The membrane permeability of cyclic peptides and peptidomimetics, which are generally larger and more complex than typical drug molecules, is likely strongly influenced by the conformational behavior of these compounds in polar and apolar environments. The size and complexity of peptides often limit their bioavailability, but there are known examples of peptide natural products such as cyclosporin A (CsA) that can cross cell membranes by passive diffusion. CsA is an undecapeptide with seven methylated backbone amides. Its crystal structure shows a “closed” twisted β-pleated sheet conformation with four intramolecular hydrogen bonds that is also observed in NMR measurements of CsA in chloroform. When binding to its target cyclophilin, on the other hand, CsA adopts an “open” conformation without intramolecular hydrogen bonds. In this study, we attempted to sample the complete conformational space of CsA in chloroform and in water by molecular dynamics simulations in order to better understand its conformational behavior in these two environments and to rationalize the good membrane permeability of CsA observed experimentally. From 10 μs molecular dynamics simulations in each solvent, Markov state models were constructed to characterize the metastable conformational states. The model in chloroform is compared to nuclear Overhauser effect NMR spectroscopy data reported in this study and taken from the literature. The conformational landscapes in the two solvents show significant overlap but also clearly distinct features

The Discovery of Novel Potent <i>trans</i>-3,4-Disubstituted Pyrrolidine Inhibitors of the Human Aspartic Protease Renin from in Silico Three-Dimensional (3D) Pharmacophore Searches

The small-molecule <i>trans</i>-3,4-disubstituted pyrrolidine <b>6</b> was identified from in silico three-dimensional (3D) pharmacophore searches based on known X-ray structures of renin–inhibitor complexes and demonstrated to be a weakly active inhibitor of the human enzyme. The unexpected binding mode of the more potent enantiomer (3<i>S</i>,4<i>S</i>)-<b>6a</b> in an extended conformation spanning the nonprime and S1′ pockets of the recombinant human (rh)-renin active site was elucidated by X-ray crystallography. Initial structure–activity relationship work focused on modifications of the hydrophobic diphenylamine portion positioned in S1 and extending toward the S2 pocket. Replacement with an optimized P3–P1 pharmacophore interacting to the nonsubstrate S3^sp cavity eventually resulted in significantly improved in vitro potency and selectivity. The prototype analogue (3<i>S</i>,4<i>S</i>)-<b>12a</b> of this new class of direct renin inhibitors exerted blood pressure lowering effects in a hypertensive double-transgenic rat model after oral administration

Structure-Based Design of Substituted Piperidines as a New Class of Highly Efficacious Oral Direct Renin Inhibitors

A <i>cis-</i>configured 3,5-disubstituted piperidine direct renin inhibitor, (<i>syn</i>,<i>rac</i>)-<b>1</b>, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine <b>31</b>. This compound showed high <i>in vitro</i> potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model

Lead Optimization of Spiropyrazolopyridones: A New and Potent Class of Dengue Virus Inhibitors

Spiropyrazolopyridone <b>1</b> was identified, as a novel dengue virus (DENV) inhibitor, from a DENV serotype 2 (DENV-2) high-throughput phenotypic screen. As a general trend within this chemical class, chiral resolution of the racemate revealed that <i>R</i> enantiomer was significantly more potent than the <i>S</i>. Cell-based lead optimization of the spiropyrazolopyridones focusing on improving the physicochemical properties is described. As a result, an optimal compound <b>14a</b>, with balanced <i>in vitro</i> potency and pharmacokinetic profile, achieved about 1.9 log viremia reduction at 3 × 50 mg/kg (bid) or 3 × 100 mg/kg (QD) oral doses in the dengue <i>in vivo</i> mouse efficacy model

Optimization of 3‑Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1

High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)­amino)­pyrimidin-4-yl)­oxazolidin-2-one as a potent inhibitor of IDH1^R132H. Synthesis of the four separate stereoisomers identified the (<i>S</i>,<i>S</i>)-diastereomer (<b>IDH125</b>, <b>1f</b>) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1^wt. Initial structure–activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood–brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (<i>S</i>,<i>S</i>)-oxazolidinone <b>IDH889</b> (<b>5x</b>) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model

Discovery of Tetrahydropyrazolopyrimidine Carboxamide Derivatives As Potent and Orally Active Antitubercular Agents

Tetrahydropyrazolo­[1,5-<i>a</i>]­pyrimidine scaffold was identified as a hit series from a <i>Mycobacterium tuberculosis</i> (Mtb) whole cell high through-put screening (HTS) campaign. A series of derivatives of this class were synthesized to evaluate their structure–activity relationship (SAR) and structure–property relationship (SPR). Compound <b>9</b> had a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse efficacy model, achieving a reduction of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. Thus, compound <b>9</b> is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB