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Lead Identification

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Lead-Seeking Approaches

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 5))

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Abstract

High quality leads provide the foundation for the discovery of successful clinical development candidates, and therefore the identification of leads is an essential part of drug discovery. Many factors contribute to the quality of a lead, including biological, physicochemical, ADME, and PK parameters. The identification of high quality leads, which are needed for successful lead optimization, requires the optimization of all of these parameters. Parallel optimization of all parameters is the most efficient way to achieve the goal of lead identification.

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Abbreviations

Aβ:

β-Amyloid

AcpS:

Acyl carrier protein synthase

AD:

Alzheimer's disease

ADME:

Absorption distribution metabolism excretion

AGP:

Alpha glycoprotein

APP:

Amyloid precursor protein

BBB:

Blood brain barrier

BBB PAMPA:

Blood brain barrier parallel artificial membrane permeability assay

BSA:

Bovine serum albumin

CCR1:

Chemokine (C-C motif) receptor 1

CDK2:

Cyclin-dependent kinase 2

CGRP:

Calcitonin gene related peptide

CHK-1:

Checkpoint kinase 1

CLint :

Intrinsic clearance

COST:

Changing one separate factor at a time

cPLA2α:

Cytosolic phospholipase A2α

CYP450:

Cytochrome P450

DMSO:

Dimethyl sulfoxide

DPP-4:

Dipeptidyl peptidase IV

FACS:

Fluorescence activated cell sorter

FLIPR:

Fluorimetric imaging plate reader

GLP-1:

Glucagon-like peptide-1

GPCR:

G-protein coupled receptor

HCV:

Hepatitis C virus

hERG:

Human ether-a-go-go-related gene

HLM:

Human liver microsomes

HMQC:

Heteronuclear multiple quantum correlation

HSA:

Human serum albumin

HTS:

High throughput screen

IKKβ:

IκB kinase-β

IP:

Intellectual property

ITK:

Interleukin-2-inducible T cell kinase

iv:

Intravenous

LC/MS:

Liquid chromatography/mass spectrometry

LE:

Ligand efficiency

MCH1:

Melanin-concentrating hormone 1

MIC:

Minimum inhibitory concentration

MVA:

Multivariate data analysis

MW:

Molecular weight

NHR:

Nuclear hormone receptor

NLM:

Nonlinear mapping

PAMPA:

Parallel artificial membrane permeability assay

PCA:

Principal component analysis

PDE5:

Phosphodiesterase 5

PGP:

P-Glycoprotein

PK:

Pharmacokinetic

PKCθ:

Protein kinase C θ

PLS:

Projection to latent structures by means of a partial least squares analysis

po:

Oral

PSA:

Polar surface area

RARβ2:

Retinoic acid β2

RLM:

Rat liver microsomes

SAR:

Structure activity relationship

SPR:

Structure property relationship

SPR:

Surface plasmon resonance

STD:

Saturation transfer difference

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Author information

Authors and Affiliations

  1. Medicinal Chemistry, Wyeth Research, 401 N. Middletown Rd., Pearl River, NY, 10965, USA

    John W. Ellingboe & Adam M. Gilbert

Authors
  1. John W. Ellingboe
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  2. Adam M. Gilbert
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Corresponding author

Correspondence to John W. Ellingboe .

Editor information

Editors and Affiliations

  1. Dept. Neuroscience Chemistry, Pfizer Global Research & Development, Eastern Point Rd., 06340, Groton CT, MS, 8220/4339, USA

    Matthew M. Hayward

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Ellingboe, J.W., Gilbert, A.M. (2009). Lead Identification. In: Hayward, M.M., et al. Lead-Seeking Approaches. Topics in Medicinal Chemistry, vol 5. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2009_2

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