Sandhya Mandlekar
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View article: A Comparative Clinical Pharmacology Analysis of FDA‐Approved Targeted Covalent Inhibitors vs. Reversible Inhibitors in Oncology
A Comparative Clinical Pharmacology Analysis of FDA‐Approved Targeted Covalent Inhibitors vs. Reversible Inhibitors in Oncology Open
Targeted covalent inhibitors (TCIs) are an emerging class of anticancer therapeutics. TCIs are designed to selectively engage their targeted proteins via covalent warheads. From the drug development standpoint, the covalent inhibition mech…
View article: A translational QSP model to characterize the preclinical pharmacodynamics of combining a KRAS G12C inhibitor with a SHP2 inhibitor
A translational QSP model to characterize the preclinical pharmacodynamics of combining a KRAS G12C inhibitor with a SHP2 inhibitor Open
View article: Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial
Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial Open
KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRA S G12C -positive CRC at 400 mg. Epidermal growth …
View article: Single-Agent Divarasib (GDC-6036) in Solid Tumors with a <i>KRAS</i> G12C Mutation
Single-Agent Divarasib (GDC-6036) in Solid Tumors with a <i>KRAS</i> G12C Mutation Open
Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).
View article: Improving Drug Delivery While Tailoring Prodrug Activation to Modulate <i>C</i><sub>max</sub> and <i>C</i><sub>min</sub> by Optimization of (Carbonyl)oxyalkyl Linker-Based Prodrugs of Atazanavir
Improving Drug Delivery While Tailoring Prodrug Activation to Modulate <i>C</i><sub>max</sub> and <i>C</i><sub>min</sub> by Optimization of (Carbonyl)oxyalkyl Linker-Based Prodrugs of Atazanavir Open
Structure-property relationships associated with a series of (carbonyl)oxyalkyl amino acid ester prodrugs of the marketed HIV-1 protease inhibitor atazanavir (1), designed to enhance the systemic drug delivery, were examined. Compar…
View article: Evolution of preclinical characterization and insights into clinical pharmacology of checkpoint inhibitors approved for cancer immunotherapy
Evolution of preclinical characterization and insights into clinical pharmacology of checkpoint inhibitors approved for cancer immunotherapy Open
Cancer immunotherapy has significantly advanced the treatment paradigm in oncology, with approvals of immuno‐oncology agents for over 16 indications, many of them first line. Checkpoint inhibitors (CPIs) are recognized as an essential back…
View article: BMS-813160: A Potent CCR2 and CCR5 Dual Antagonist Selected as a Clinical Candidate
BMS-813160: A Potent CCR2 and CCR5 Dual Antagonist Selected as a Clinical Candidate Open
BMS-813160 (compound 3) was identified as a potent and selective CCR2/5 dual antagonist. Compound 3 displayed good permeability at pH = 7.4 in PAMPA experiments and demonstrated excellent human liver microsome stability. Phar…
View article: Role of a Mitogen-activated Protein Kinase Pathway in the Induction of Phase II Detoxifying Enzymes by Chemicals
Role of a Mitogen-activated Protein Kinase Pathway in the Induction of Phase II Detoxifying Enzymes by Chemicals Open
Mitogen-activated protein kinase (MAPK) cascades are activated by diverse extracellular signals and participate in the regulation of an array of cellular programs. In this study, we investigated the roles of MAPKs in the induction of phase…
View article: Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2
Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2 Open
To improve the metabolic stability profile of BMS-741672 (1a), we undertook a structure-activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of 2d (BMS-753426) as…
View article: Design, Synthesis, and Pharmacokinetic Evaluation of Phosphate and Amino Acid Ester Prodrugs for Improving the Oral Bioavailability of the HIV-1 Protease Inhibitor Atazanavir
Design, Synthesis, and Pharmacokinetic Evaluation of Phosphate and Amino Acid Ester Prodrugs for Improving the Oral Bioavailability of the HIV-1 Protease Inhibitor Atazanavir Open
Phosphate and amino acid prodrugs of the HIV-1 protease inhibitor (PI) atazanavir (1) were prepared and evaluated to address solubility and absorption limitations. While the phosphate prodrug failed to release 1 in rats, the introduction o…
View article: Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672
Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672 Open
We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion channel selectivity but poor oral bioavaila…
View article: Coupling of an Acyl Migration Prodrug Strategy with Bio-activation To Improve Oral Delivery of the HIV-1 Protease Inhibitor Atazanavir
Coupling of an Acyl Migration Prodrug Strategy with Bio-activation To Improve Oral Delivery of the HIV-1 Protease Inhibitor Atazanavir Open
HIV-1 protease inhibitors (PIs), which include atazanavir (ATV, 1), remain important medicines to treat HIV-1 infection. However, they are characterized by poor oral bioavailability and a need for boosting with a pharmacokinetic enhancer, …
View article: Selective <i>I</i><sub>Kur</sub> Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide
Selective <i>I</i><sub>Kur</sub> Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide Open
We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon …
View article: Coproporphyrin-I: A Fluorescent, Endogenous Optimal Probe Substrate for ABCC2 (MRP2) Suitable for Vesicle-Based MRP2 Inhibition Assay
Coproporphyrin-I: A Fluorescent, Endogenous Optimal Probe Substrate for ABCC2 (MRP2) Suitable for Vesicle-Based MRP2 Inhibition Assay Open
View article: Unmasking the Role of Uptake Transporters for Digoxin Uptake Across the Barriers of the Central Nervous System in Rat
Unmasking the Role of Uptake Transporters for Digoxin Uptake Across the Barriers of the Central Nervous System in Rat Open
The role of uptake transporter (organic anion–transporting polypeptide [Oatp]) in the disposition of a P-glycoprotein (P-gp) substrate (digoxin) at the barriers of central nervous system, namely, the blood-brain barrier (BBB), blood-spinal…
View article: Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain
Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain Open
To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase…
View article: Discovery of 5-Phenyl-<i>N</i>-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine as a Potent<i>I</i><sub>Kur</sub>Inhibitor
Discovery of 5-Phenyl-<i>N</i>-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine as a Potent<i>I</i><sub>Kur</sub>Inhibitor Open
A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-…
View article: Absorption and cleavage of enalapril, a carboxyl ester prodrug, in the rat intestine: in vitro, in situ intestinal perfusion and portal vein cannulation models
Absorption and cleavage of enalapril, a carboxyl ester prodrug, in the rat intestine: in vitro, in situ intestinal perfusion and portal vein cannulation models Open
In recent years prodrug strategy has been used extensively to improve the pharmacokinetic properties of compounds exhibiting poor bioavailability. Mechanistic understanding of the absorption and the role of intestine and liver in the activ…
View article: Discovery of a Potent and Orally Bioavailable Dual Antagonist of CC Chemokine Receptors 2 and 5
Discovery of a Potent and Orally Bioavailable Dual Antagonist of CC Chemokine Receptors 2 and 5 Open
We describe the hybridization of our previously reported acyclic and cyclic CC chemokine receptor 2 (CCR2) antagonists to lead to a new series of dual antagonists of CCR2 and CCR5. Installation of a γ-lactam as the spacer group and a quina…