Andrew T. Pudzianowski

MP2/6‐311++G(d,p) study of ten ionic hydrogen‐bonded binary systems: Structures, normal modes, thermodynamics, and counterpoise energies

Fully optimized structures, normal vibrational modes, and thermodynamic functions were obtained at the MP2/6‐311++G(d,p) level for the following ionic hydrogen‐bonded systems: H3O+/H2O, NH+4/H2O, NH+4/NH3, CH3NH+3/H2O, CH3NH+3/NH3, OH−/H2O, CH3O−/H2O, cyanide/H2O, HCC−/H2O, and formate/H2O. The calculated ΔH fell within error limits of experimental values for all but OH−/H2O and the two NH3 complexes. In the latter cases expansion of the polarization basis to (2d,2p) satisfactorily improved the model, but for OH−/H2O increasing the level of correlation to MP4 was more important. Where comparison was possible, optimized structures were quite similar to those obtained at MP2/6‐31+G(d,p) by other workers. All the complexes examined here have a hydrogen bond stretching mode in the 200–350 cm−1 range which may contribute to proton transfer, and whose frequency correlates qualitatively with the acid strength of the H‐bond donor. For the cyanide/H2O system, it is not possible to choose between CN−/H2O and NC−/H2...

Design, structure-activity relationships, X-ray crystal structure, and energetic contributions of a critical P1 pharmacophore: 3-chloroindole-7-yl-based factor Xa inhibitors.

An indole-based P1 moiety was incorporated into a previously established factor Xa inhibitor series. The indole group was designed to hydrogen-bond with the carbonyl of Gly218, while its 3-methyl or 3-chloro substituent was intended to interact with Tyr228. These interactions were subsequently observed in the X-ray crystal structure of compound 18. SAR studies led to the identification of compound 20 as the most potent FXa inhibitor in this series (IC(50) = 2.4 nM, EC(2xPT) = 1.2 microM). An in-depth energetic analysis suggests that the increased binding energy of 3-chloroindole-versus 3-methylindole-containing compounds in this series is due primarily to (a) the more hydrophobic nature of chloro- versus methyl-containing compounds and (b) an increased interaction of 3-chloroindole versus 3-methylindole with Gly218 backbone. The stronger hydrophobicity of chloro- versus methyl-substituted aromatics may partly explain the general preference for chloro- versus methyl-substituted P1 groups in FXa, which extends beyond the current series.

Aromatic isosteres as conformational probes for an isoprenyl subunit: application to inhibitors of squalene synthase

Abstract A series of aromatic isosteres of the farnesyl chain of potent squalene synthase inhibitor 1 were prepared and evaluated. The results are consistent with the local conformation indicated in structure 2 .

Stereoelectronic effects in nucleophilic addition to a bicyclic ketone: an interpretation

Abstract Addition of nucleophiles to the ketone 6 occurred in most cases from the sterically more hindered face of the carbonyl group. These results are interpreted in light of a detailed calculation of the electrostatic potential of 6 .

Synthesis of Biologically Active Piperidine Metabolites of Clopidogrel: Determination of Structure and Analyte Development

Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed.

Comment on ‘‘The protonated water dimer: Extensive theoretical studies of H5O+2’’ [J. Chem. Phys. 101, 4878 (1994)]

An inappropriate comparison in the title article between a calculated D0 and one group of experimental dissociation enthalpies is pointed out. The quoted D0 is used to derive a ΔH of 35.0 kcal/mol, in good agreement with other high‐level ab initio results and a different group of experimental values.

Conformationally constrained calcium channel blockers: novel mimics of 1-benzazepin-2-ones.

In order to test a hypothesis that the seven-membered ring of the benzothiazepinone (diltiazem) and benzazepinone calcium channel blockers serves primarily to orient two critical pharmacophores in space, a series of novel, conformationally constrained bicyclo[2.2.2]octyl amines 3 which severely restrict the relative orientations available to the amine and methoxyphenyl groups was prepared. All compounds which positioned the pharmacophores on the same face of the molecule demonstrated vasorelaxant activity and affinity for the diltiazem receptor equal to or greater than racemic diltiazem 1 or the corresponding benzazepione 2. In addition, compound 3d was equipotent to (+)-diltiazem in its ability to reduce ischemic/reperfusion injury in an in vitro model of myocardial ischemia. However, 3d is significantly less cardiodepressive at an equivalent antiischemic dose. Therefore, the original receptor binding hypothesis led to the design and synthesis of novel calcium channel blockers with unique biological properties.

Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.

Conformationally-restricted analogs of TXA2 antagonist SQ 33,961: Receptor binding conformation of the carboxyl sidechain

Abstract Two distinct conformational families, exemplified by 1 and 2, of thromboxane A2 (TxA2 receptor antagonist SQ 33,961 have been determined by molecular modeling. Synthesis and biological evaluation of confromationally-restricted mimic 3Z suggested that the hairpin conformer, 1, is the bioactive conformation.