Optimizing Potency for Nevirapine: The Drug that Saved

11/19/2014

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Upcoming ACS Webinars www.acs.org/acswebinars

Thursday, December 4, 2014

“Salvaging Carbon Dioxide: Finding Value Beyond the Smokestack” Dr. Sam Rushing, President, Advanced Cryogenics Dr. Joseph Fortunak, Professor of Chemistry, Howard University


“Chemistry & the Economy: 2014 YearEnd Review” Paul Hodges, Chairman, International eChem Dr. William Carroll, Vice President, Industry Issues for Occidental Chemical Corporation


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“Optimizing Potency for Nevirapine: The Drug that Saved Children from AIDS”

Dr. Joseph Fortunak Dr. Rebecca Anderson

Professor of Chemistry, Howard University

Freelance Medical Writer and Author



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11/19/2014

Optimizing Potency for Nevirapine: The Drug that Saved Children from AIDS

Rebecca J. Anderson, Ph.D. November 20, 2014 13

Safe Harbor Statement

All data presented in the webinar are in the public domain. All opinions expressed are those of the presenter and should not be assumed to reflect the official corporate position of the American Chemical Society or any pharmaceutical sponsor.

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Audience Survey Question What do you remember about the history of HIV/AIDS? • I remember seeing people with AIDS • I know what HIV/AIDS is, but I don’t remember the epidemic • I’d like to learn more about HIV/AIDS • Where I live HIV/AIDS is common

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Acquired Immune Deficiency Syndrome Human Immunodeficiency Virus

CD4 T-helper lymphocytes • • • • • •

Pneumocystis pneumonia Kaposi’s sarcoma Oral candidiasis (thrush) CMV retinitis Hepatitis Parasitic diarrhea

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1996 HAART implementation

Audience Survey Question In the United States for the past decade, the number of HIV-infected people has: • increased • remained constant • declined

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Mother-to-Child Transmission of HIV

infected

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ACTG 076: AZT results

Catherine Wilfert

Connor et al, NEJM 331: 1173-1180 (1994)

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ACTG 076: AZT regimen pregnancy

labor/delivery

postnatal

mother

Oral, 5x/day

14 weeks to Term

Intravenous (6-18 hrs.)

infant

Oral, 4x/day

6 weeks

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Goal: non-nucleoside RT inhibitor • HIV-RT enzyme assay • High Throughput Screening Shattock and Rosenberg, HIV from biology to prevention and treatment. Cold Spring Harbor Press, 2012, pp. 513-514

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pirenzepine O

H N

M1 selective antagonist Treatments: Peptic ulcers ↓ Gastric secretion ↓ Smooth muscle spasm

N

N

Gastrozepin®

O N N CH3

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First active compound

O

H N

IC50 = 6000 nM

N N CO2-t-Bu

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First Lead Compound

CH3

O

IC50 = 350 nM

N

N

N CH3

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CH3

IC50 = 125 nM

O

more potent more soluble

N

N N

N

CH3

dipyrido

N-11 ethyl optimal

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CH3

N-5 demethylation

O

IC50 = 125 nM

N

more potent more soluble short acting

N N

N CH3

N-11 deethylation

(inactive)

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(stable)

CH3

O

IC50 = 120 nM

N

more potent more stable

N N

N N-11 cyclopropyl

(stable)

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nevirapine (potency)

H N

CH3

Final Lead Compound

O

IC50 = 84 nM more potent more stable ↑ bioavailability

N N

N

32

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nevirapine

O

H N

CH3

pirenzepine

N N

O

H N

N

N

N O

N N CH3 33

Shattock and Rosenberg, HIV from biology to prevention and treatment. Cold Spring Harbor Press, 2012, pp. 513-514

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Mother-to-Child Transmission of HIV in utero childbirth

infected breastfeeding

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ACTG 250: Concentration-time plots for infants receiving booster 2 mg/kg dose 48-72 hr. after birth; mothers received 200 mg. NVP, nevirapine; time 0, birth. Mirochnick et al, J Infect Dis 178: 368-374 (1998) 36

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J. Brooks Jackson

Laura Guay 37

13% 25%

HIVNET 012: Kaplan-Meier estimates of proportion of babies free from HIV-1 infection through 18 months Guay et al, Lancet 354: 795-802 (1999)

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AZT vs. Nevirapine AZT

Nevirapine

Clinical Trial

ACTG 076

HIVNET 012

Half-life

0.5 – 3 hr.

45 hr.

# maternal doses

700

1

# infant doses

168

1

Cost

$815

$4

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PEPFAR

President George W. Bush announces a new Mother and Child HIV Prevention Initiative in the Rose Garden June 19. Standing by the President from, left to right, are Secretary of Treasury Paul O'Neill, Secretary of Health and Human Services Tommy Thompson and Secretary of State Colin Powell. 40

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South Africa: Activist Pressure

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Audience Survey Question What percentage of HIV-positive pregnant women in Africa currently receive AIDS drug treatment? • • • •

26% 58% 68% 93%

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For More Details….

McFarland Publishing Amazon.com Barnes & Noble

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Dr. Joseph Fortunak Professor of Chemistry, Howard University

Dr. Rebecca Anderson Freelance Medical Writer and Author



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11/19/2014


Dr. Joseph Fortunak Professor of Chemistry, Howard University

Dr. Rebecca Anderson Freelance Medical Writer and Author



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“ACS Webinars allow me to show my students how chemistry is truly related to everything around them - the medicines they take, the foods they eat, the products they utilize, etc. I enjoy participating in the webinars with them to expose them to current topics and so they can listen to scientists working in fields that may interest them.”

Todd Smeltz, Math & Chemistry Teacher, Upper Dauphin Area School District

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Optimizing Potency for Nevirapine: The Drug that Saved

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