Jayaraman Chandrasekhar

Strategies and tactics for optimizing the Hit-to-Lead process and beyond—A computational chemistry perspective

The Hit-to-Lead-to-Candidate process continues to evolve rapidly, and while technological advances offer much potential, the reality often pales to the promise. Conversely, strategies and tactics implementing existing technologies may result in more benefit in the end. This article focuses on some of the thinking and approaches that may improve the efficiency and effectiveness of the beginnings of the drug discovery path. From the perspective of computational chemists, different types of strategy and philosophy of approach will be treated including: considerations of early lead choices, strategies for improving poor leads, multivariate optimization, opportunities for informatics, and engineering good decisions.

The design, synthesis and structure–activity relationships of 1-aryl-4-aminoalkylisoquinolines: A novel series of CRF-1 receptor antagonists

The design, synthesis and structure-activity relationships of a novel series of CRF-1 receptor antagonist, the 1-aryl-4-alkylaminoisoquinolines, is described. The effects of substitution on the aromatic ring, the amino group and the isoquinoline core on CRF-1 receptor binding were investigated.

Design, synthesis, and discovery of 5-piperazinyl-1,2,6,7-tetrahydro-5H-azepino[3,2,1-hi]indol-4-one derivatives: a novel series of mixed dopamine D2/D4 receptor antagonist.

5-piperazinyl-1,2,6,7-tetrahydro-5H-azepino[3,2,1-hi]indol-4-one derivatives were designed, synthesized, and identified as a new series of mixed dopamine D(2)/D(4) receptor antagonists. This series featured a rigid tricyclic ring system as an important pharmacophore core structure for high binding affinity. Molecular modeling studies are also described.

1-Benzylbenzimidazoles: The discovery of a novel series of bradykinin B 1 receptor antagonists

The design, synthesis, and structure-activity studies of a novel series of BK B(1) receptor antagonists based on a 1-benzylbenzimidazole chemotype are described. A number of compounds, for example, 38g, with excellent affinity for the cynomolgus macaque and rat bradykinin B(1) receptor were discovered.

2-Arylpyrimidines : Novel CRF-1 receptor antagonists

The design, synthesis and structure-activity relationship studies of a novel series of CRF-1 receptor antagonists, the 2-arylpyrimidines, are described. The effects of substitution on the aromatic ring and the pyrimidine core on CRF-1 receptor binding were investigated. A number of compounds with K(i) values below 10 nM and lipophilicity in a minimally acceptable range for a CNS drug (cLogP<5) were discovered.

Selectivity switch between FAK and Pyk2: Macrocyclization of FAK inhibitors improves Pyk2 potency

Herein, we describe the synthesis of Pyk2 inhibitors via macrocyclization of FAK and dual Pyk2-FAK inhibitors. We identified macrocycle 25a as a highly potent Pyk2 inhibitor (IC50=0.7nM), with ∼175-fold improvement in Pyk2 potency as compared to its acyclic counterpart. In many cases, macrocyclization improved Pyk2 potency while weakening FAK potency, thereby improving the Pyk2/FAK selectivity ratio for this structural class of inhibitors. Various macrocyclic linkers were studied in an attempt to optimize Pyk2 selectivity. We observed macrocyclic atropisomerism during the synthesis of 19-membered macrocycles 10a-d, and successfully obtained crystallographic evidence of one atropisomer (10a-AtropB) preferentially bound to Pyk2.

Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3-Kinase (PI3K) β Inhibitor

Atropisomerism is a type of axial chirality in which enantiomers or diastereoisomers arise due to hindered rotation around a bond axis. In this manuscript, we report a case in which torsional scan studies guided the thoughtful creation of a restricted axis of rotation between two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) β inhibitor, generating a pair of atropisomeric compounds with significantly different pharmacological and pharmacokinetic profiles. Emblematic of these differences, the metabolism of inactive ( M)-28 is primarily due to the cytosolic enzyme aldehyde oxidase, while active ( P)-28 has lower affinity for aldehyde oxidase, resulting in substantially better metabolic stability. Additionally, we report torsional scan and experimental studies used to determine the barriers of rotation of this novel PI3Kβ inhibitor.

Discovery of a Phosphoinositide 3-Kinase (PI3K) β/δ Inhibitor for the Treatment of Phosphatase and Tensin Homolog (PTEN) Deficient Tumors: Building PI3Kβ Potency in a PI3Kδ-Selective Template by Targeting Nonconserved Asp856

Phosphoinositide 3-kinase (PI3K) β signaling is required to sustain cancer cell growth in which the tumor suppressor phosphatase and tensin homolog (PTEN) has been deactivated. This manuscript describes the discovery, optimization, and in vivo evaluation of a novel series of PI3Kβ/δ inhibitors in which PI3Kβ potency was built in a PI3Kδ-selective template. This work led to the discovery of a highly selective PI3Kβ/δ inhibitor displaying excellent pharmacokinetic profile and efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model.