Sue-Ing Lin

Piperazine-based CCR5 antagonists as HIV-1 inhibitors. I: 2(S)-methyl piperazine as a key pharmacophore element.

Optimization of the piperidino-piperazines 1 and 2 provided early leads 3 and 4, which showed good activity in the CCR5-RANTES binding assay and in antiviral assays. A systematic study around these structures showed that the 2(S)-methyl piperazine is essential for CCR5 affinity, which is further enhanced by forming the 2,6-dimethyl benzamide of the piperidine.

Controlling benzylic functionality and stereochemistry: 2. Synthesis of the pseudopterosin aglycone

Homologation, cyclisation, and reduction converted the tetralin (2) to the hexahydrophenalenol (8), which was methylated to afford (19), via alkoxide-directed metalation. The degree of stereoselectivity resulting from reactions of (19) and congeners with allylsilane - Lewis acid combinations was markedly dependent upon substitution patterns, whereas Et2AlCN-SnCl4 produced pseudoaxial nitriles. The trimethyl nitrile (24) was elaborated to the pseudopterosin aglycone (4).

Piperazine-based CCR5 antagonists as HIV-1 inhibitors. III: synthesis, antiviral and pharmacokinetic profiles of symmetrical heteroaryl carboxamides ☆

The unsymmetrical nicotinamide-N-oxide moiety in compound 1 was replaced with symmetrical isonicotinamides as well as 4,6-dimethyl pyrimidine-5-carboxamides. Compound 16 from the latter set reduced the number of rotamers, improved potency of inhibiting UIV entry, slightly diminished the affinity for the muscarine receptors and showed very good oral absorption.

(−)-SCH 57939: synthesis and pharmacological properties of a potent, metabolically stable cholesterol absorption inhibitor

Abstract Previous SAR studies of C-3 side chain modified analogs of (−)-SCH 48461, 1,3,4 as well as information concerning the metabolic stability this series, enabled us to design a cholesterol absorption inhibitor (i.e., (−) 2a, SCH 57939) with tenfold higher potency and greatly enhanced metabolic stability. The synthesis and pharmacological profile, including the role of relative stereochemistry at both the C3 and 1′ positions in determining the SAR of these compounds, will be discussed.

Substituted 2-(R)-Methyl piperazines as muscarinic M2 selective ligands

A novel series of 2-(R)-methyl-substituted piperazines (e.g., 2) is described. They are potent M(2) selective ligands that have >100-fold selectivity versus the M(1) receptor. In the rat microdialysis assay, compound 14 showed significantly enchanced levels of acetylcholine after oral administration.

Gamma-lactams and related compounds as cholesterol absorption inhibitors: homologs of the beta-lactam cholesterol absorption inhibitor SCH 484611

Abstract Our search for potent cholesterol absorption inhibitors led to the discovery of the β-lactam SCH 48461. Structure activity relationship studies prompted us to this study of γ-lactams, ring homologs of β-lactam SCH 48461, to determine their potential as cholesterol absorption inhibitors. The results indicate that the γ-lactams have moderate cholesterol absorption inhibitory properties.

Synthesis of racemic, 2-(alkylthio)-6-(1-hydroxyethyl) penems; attempted penem synthesis via copper (I) - promoted cyclisations

Abstract Stereocontrolled syntheses of the diastereoisomeric 6-(1-hydroxyethyl)-2-ethylthio and 2-(2-aminoethylthio)-penem-3-carboxylates from a common monocyclic azetidinone precursor are described. Cu (I)-promoted cyclisation of suitable N/C-3 secopenems is shown to yield “isopenems” (7-oxo-2-thia-1-azabicyc1o[3.2.0]-hept-3-enes) as the sole bicyclic product.

Indolocarbazoles. 1. Total synthesis and protein kinase inhibiting characteristics of compounds related to K-252c.

Abstract The condensation of indolo[2,3-a]-carbazole ( 12 ) with 2,5-dimethoxytetrahydrofuran derivatives gave cyclofuranosylated compounds (e.g. 13 ), which were converted via dibromocompounds to the dinitriles (e.g. 25 ). Hydrolysis, hydrolysis-reduction and thiolysis afforded imides, lactams (e.g. 27 ) and their thio analogs. These compounds were potent inhibitors of the protein kinase C family.

Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity

Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinsons disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.

Tetrahydroquinoline sulfonamides as vasopressin 1b receptor anatgonists

Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists that possessed moderate to high selectivity over other receptors.