532 - Med Chem Ii - Exam I - Parts 2C, 2D, 2E, & 2F

Front 1

What are the five drugs currently approved for AD?

Back 1

The five drugs currently approved for AD include one NMDA receptor antagonist, Memantine, and four cholinesterase inhibitors Donepezil, Galantamine, Rivastigmine, and Tacrine.

Front 2

What do cholinesterase inhibitors do?

Back 2

Cholinesterase inhibitors hinder the hydrolysis of the neurotransmitter acetylcholine by cholinesterase, thus potentiating cholinergic transmission.

Front 3

What are amyloid plaques?

Back 3

Amyloid plaques are dense, proteinaceous cores containing, as their primary component, amyloid beta, which is derived from the cleavage of the amyloid precursor protein (APP) found on cell surfaces.

Front 4

What are neurofibrillary tangles?

Back 4

Neurofibrillary tangles are insoluble, twisted fibers - found inside the neurons - that consist primarily of a hyperphosphorylated form of the microtubule-associated protein called TAU.

Front 5

What are the three facets of the the blood brain barrier that present a challenge in the development of drugs that target the brain?

Back 5

1) Tight Junctions & Adheres Junctions, 2) P-Glycoprotein (p-gp) & Multidrug Resistance-Associated Proteins (MRPs), 3) Intracellular & Extracellular Enzymes

Front 6

What role do tight junctions and adherens junctions play in creating the blood brain barrier?

Back 6

Tight junctions (TJs) make the brain inaccessible for polar molecules, unless they are transferred by transport pathways. Adherens junctions (AJs) stabilize cell-cell interactions in the junctional zone.

Front 7

What role do P-glycoprotein (p-gp) and Multidrug Resistance-Associated Proteins (MRPs) play in creating the blood brain barrier?

Back 7

p-gp and MRPs can efflux (pump out) drugs and other substances.

Front 8

How do intracellular and extracellular enzymes play a role in creating the blood brain barrier?

Back 8

Intracellular and extracellular enzymes may degrade drugs and other substances.

Front 9

Describe the main steps, including the proteases, leading to amyloid beta production.

Back 9

The general process involves two cleavages of APP, one by beta-secretase (BACE) and another by gamma-secretase, to produce amyloid beta.

Front 10

What protease can prevent the formation of amyloid beta?

Back 10

Cleavage of the APP by alpha-secretase precludes formation of amyloid beta.

Front 11

Which are the protease targets for AD and why?

Back 11

The protease targets for AD are inhibition of beta-secretase (BACE) and gamma-secretase - as the action of each on APP is needed to form amyloid beta - and activation of alpha-secretase, which prevents amyloid beta formation when it cleaves APP.

Front 12

What are gamma-secretase modulators?

Back 12

The non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen, indomethacin, and sulindac sulfide subtly alter gamma-secretase activity in a manner decreasing the formation of the more fibrillogenic amyloid beta 42 isoform and increasing the formation of the shorter amyloid beta 37, 38, & 39 isoforms instead.

Front 13

What are the three major drug classes on the market for osteoporosis.

Back 13

The three major drug classes on the market for osteoporosis are bisphosphonates, calcitonins, and SERMs (selective estrogen receptor modulators).

Front 14

What do osteoblast cell and osteoclast cell do?

Back 14

Osterblast cells build bone, while osterclast cells resorb bone. [To keep these straight, think of the B in osterBlast standing for "build" and the C in osteoClast standing for "cut" or "corrode."]

Front 15

What is the role of cathepsin K in the bone remodeling cycle?

Back 15

The cysteine protease cathepsin K is the major enzyme in osterclasts. Its substrate is Type I Collagen, which constitutes 95% of the organic bone matrix.

Front 16

How was the hypothetical ketone cathepsin K inhibitor designed based on leupeptin and another aldehyde?

Back 16

Both aldehydes inhibit cathepsin K. One interacts with the S1, S2, & S3 sites, while the other interacts with S1', S2', & S3' sites. The hypothetical ketone was designed by connecting the two structures through the, formerly aldehyde, carbonyl of each.

Front 17

How was conformational restriction used in the design of cathepsin K inhibitors and what are the potential benefits of conformational restriction?

Back 17

The ketone entity of a lead compound was incorperated into 5- and 6-membered ring systems placing the ketone substituents into either of two fixed conformations. This strategy allowed the identification of derivatives having a greater potency of inhibition and a higher selectivity for cathepsin K versus other cathepsins.

Front 18

What functional groups, found in cysteine protease inhibitors, will react with cysteine in the active site?

Back 18

Aldehydes, Ketones, & Nitriles. [Be prepared to draw the resulting, reversible intermediate of such reactions on the exam!]

Front 19

What two strategies were utilized to block sites of CYP450 metabolism in a lead compound to develop odanacatib?

Back 19

1) Replacement of the hydrogen on the tertiary carbon of an isopropyl group with a fluorine, to preclude oxidation of the tertiary carbon through addition of a hydroxyl group, & 2) The addition of a cyclopropyl ring in place of the methylene unit adjacent to a nitrile in order to hinder its hydrolysis to a carboxylic acid. [Consult lecture notes for visual details!]

Front 20

What is the function of proteasome?

Back 20

The main function of proteasome is to degrade unneeded or damaged proteins by hydrolyzing peptide bonds. It plays a key role in the proliferation of myeloma cells by degrading the I-KB protein that normally inhibits the NF-KB protein to prevent it from translocating to the nucleus, where it activates the transcription of anti-apototic factors.

Front 21

What is ubiquitination?

Back 21

Ubiquitination - referred to as the "kiss of death" for a protein - is the process by which a protein is tagged with ubiquitin, which signals the protein transport machinery to ferry the protein to the proteasome for degradation.

Front 22

What factors may trigger protein ubiquitination?

Back 22

Certain primary sequences automatically trigger protein ubiquitination, as can protein phosphorylation, hydroxylation of a proline residue, misfolding of a protein, and glycosylation of a protein.

Front 23

What is the target and mechanism of action for bortezomib.

Back 23

Bortezomib blocks the protein degrading action of proteosome, preventing it from degrading the I-KB protein that inhibits NF-KB, thereby precluding the activation of NF-KB that is essential for myeloma cell development and survival.

Front 24

What are the two major enzymes in the renin-angiotensin system?

Back 24

There are two major enzymes of the renin-angiotensin system are the aspartic protease Renin, which cleaves angiotensinogen to form angiotensin I, and the zinc metalloprotease Angiotensin-Converting Enzyme (ACE), which cleaves angiotensin I to form angiotensin II.

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Front 26

Why was Carboxypeptidase A (CPA) used as a model for designing ACE inhibitors?

Back 26

At the time of the first efforts to develop an ACE inhibitor, the structure of ACE was unknown. The structure of CPA, on the other hand, had already been established. The two enzymes shared three key similarities: 1) both are zinc proteases, 2) both cleave carboxy terminal residues, & 3) both require a negative charge (the terminal carboxylate) in the substrate. This is why CPA was used as the model for designing ACE inhibitors.

Front 27

What are the two main binding interactions that both CPA and ACE share with their respective substrates and inhibitors?

Back 27

For both CPA and ACE, a positively charged residue, such as arginine, binds to a terminal carboxylate ion of either the substrate or the inhibitor. Both CPA and ACE also have a Zn2+ ion that either binds the oxygen of the carbonyl at the site of cleavage in the substrate or to a second carboxylate ion (or a thiol group) in an inhibitor designed to mimic this key portion of the substrate's structure.

Front 28

Briefly describe the three steps in the rational design of Captopril.

Back 28

1) A nonapeptide (9 amino acids (aa)) from a snake venom, called teprotide, that inhibits ACE was simplified to a tripeptide (3 aa) that proved to be active, 2) The tripeptide was further symplified to succinyl-L-proline, which also proved active, & 3) the succinyl carboxylate unit was replaced with a metal-binding thiol group to create captopril.

Front 29

What is the source of side effects for Captopril?

Back 29

Under oxidative conditions, the thiol group of captopril can react with cysteine residues of proteins to form a disulfide bond, thereby altering the structure and function of such proteins.

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