11/19/2014
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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
Thursday, December 11, 2014
“Chemistry & the Economy: 2014 YearEnd Review” Paul Hodges, Chairman, International eChem Dr. William Carroll, Vice President, Industry Issues for Occidental Chemical Corporation
Contact ACS Webinars ® at
[email protected] 11
“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
Recordings will be available to ACS members after three weeks
www.acs.org/acswebinars Contact ACS Webinars ® at
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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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11/19/2014
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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11/19/2014
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
18
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11/19/2014
Mother-to-Child Transmission of HIV
infected
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11/19/2014
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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11/19/2014
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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11/19/2014
First active compound
O
H N
IC50 = 6000 nM
N N CO2-t-Bu
27
First Lead Compound
CH3
O
IC50 = 350 nM
N
N
N CH3
28
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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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11/19/2014
(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
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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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11/19/2014
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
39
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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11/19/2014
South Africa: Activist Pressure
41
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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11/19/2014
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For More Details….
McFarland Publishing Amazon.com Barnes & Noble
44
22
11/19/2014
“Optimizing Potency for Nevirapine: The Drug that Saved Children from AIDS”
Dr. Joseph Fortunak Professor of Chemistry, Howard University
Dr. Rebecca Anderson Freelance Medical Writer and Author
Recordings will be available to ACS members after three weeks
www.acs.org/acswebinars Contact ACS Webinars ® at
[email protected] 45
®
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
Thursday, December 11, 2014
“Chemistry & the Economy: 2014 YearEnd Review” Paul Hodges, Chairman, International eChem Dr. William Carroll, Vice President, Industry Issues for Occidental Chemical Corporation
Contact ACS Webinars ® at
[email protected] 46
23
11/19/2014
“Optimizing Potency for Nevirapine: The Drug that Saved Children from AIDS”
Dr. Joseph Fortunak Professor of Chemistry, Howard University
Dr. Rebecca Anderson Freelance Medical Writer and Author
Recordings will be available to ACS members after three weeks
www.acs.org/acswebinars Contact ACS Webinars ® at
[email protected] How has ACS Webinars benefited you?
47
®
“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
Be a featured fan on an upcoming webinar! Write to us @
[email protected] 48
24
11/19/2014
facebook.com/acswebinars
@acswebinars youtube.com/acswebinars
49
Benefits of ACS Membership Chemical & Engineering News (C&EN) The preeminent weekly news source.
NEW! Free Access to ACS Presentations on Demand® ACS Member only access to over 1,000 presentation recordings from recent ACS meetings and select events.
NEW! ACS Career Navigator Your source for leadership development, professional education, career services, and much more.
www.acs.org/2joinACS
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11/19/2014
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ACS Webinars does not endorse any products or services. The views expressed in this presentation are those of the presenter and do not necessarily reflect the views or policies of the American Chemical Society.
Contact ACS Webinars ® at
[email protected] 51
®
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
Thursday, December 11, 2014
“Chemistry & the Economy: 2014 YearEnd Review” Paul Hodges, Chairman, International eChem Dr. William Carroll, Vice President, Industry Issues for Occidental Chemical Corporation
Contact ACS Webinars ® at
[email protected] 52
26