Pharmaceutical Chemistry III Lecture 3 PDF

PHARMACEUTICAL CHEMISTRY III LECTURE 3 PROF. DR. ASHRAF ABADI PHCMt774 Prof. Ashraf Abadi 1  BY THE END OF LECTURE 3, THE STUDENT WILL BE ABLE TO: Domain 1: Fundamental Knowledge 1-1- Competency Key Elements 1-1-1 Demonstrate knowledge o...

PHARMACEUTICAL CHEMISTRY III LECTURE 3 PROF. DR. ASHRAF ABADI PHCMt774 Prof. Ashraf Abadi 1  BY THE END OF LECTURE 3, THE STUDENT WILL BE ABLE TO: Domain 1: Fundamental Knowledge 1-1- Competency Key Elements 1-1-1 Demonstrate knowledge of the specific pathways of ACE inhibitors, AT1 antagonists and Renin inhibitors metabolism. 1-1-2 Integrate the theoretical concepts and methodology of different principles of drug design (Structure-based/ Ligand-based). 1-1-3 Use the proper pharmaceutical & medical terms, abbreviations & symbols in pharmaceutical chemistry practice. 1-1-4 Articulate knowledge about various properties of ACE inhibitors, AT1 antagonists and Renin inhibitors , including mechanisms of actions, therapeutic uses, dosage, contra-indications and drug interactions. 1-1-5 Show the relationship between the properties of ACE inhibitors, AT1 antagonists and Renin inhibitors and their chemical structure including the relationship between physicochemical properties and activity of various drugs. 1-1-6 Utilize scientific literature, and collect and interpret information to enhance professional decision Domain 2: Professional & Ethical Practice 2-2- Competency Key Elements 2-2-1 Correlate between essential pharmacophoric features of ACE inhibitors, AT1 antagonists and Renin inhibitors and their activity (Structure-Activity Relationship), safety/toxicity profile. 2-2-2 Select the appropriate methods of synthesis, purification, and identification of active drugs. 2-2-3 Apply the pharmacological basics of therapeutics in the proper selection and use of ACE inhibitors, AT1 antagonists and Renin inhibitors in various disease conditions. 2-2-4 Weigh activity versus side effects of ACE inhibitors, AT1 antagonists and Renin inhibitors , design of novel medicinal agents, and suggest suitable dosage forms based on the chemical features of drugs. 2-4- Competency Key Elements 2-4-4 Recognize the activity & toxicity profile of various drugs, deduced from their structure & metabolism. Domain 3: Pharmaceutical Care 3-2- Competency Key Elements 3-2-1 Integrate the different synthetic and analytical techniques for synthesis and analysis of ACE inhibitors, AT1 antagonists and Renin inhibitors. Domain 4: Personal Practice 4-1- Competency Key Elements 4-1-3 Demonstrate critical thinking, and problem solving regarding solving extra exercises in tutorials, assignments, and lecture slides. 4-2- Competency Key Elements 4-2-1 Demonstrate critical thinking, problem solving and decision making regarding the activity, suitable use and delivery route of each drug. 4-3- Competency Key Elements 4-3-1 Practice independent learning needed for continuous professional development via exploring the references indicated in the lecture slides PHCMt774 Prof. Ashraf Abadi 2 RENIN ANGIOTENSIN ALDOSTERONE SYSTEM (RAAS) PHCMt774 Prof. Ashraf Abadi 3 RENIN ANGIOTENSIN ALDOSTERONE SYSTEM (RAAS) PHCMt774 Prof. Ashraf Abadi 4  RENIN ANGIOTENSIN ALDOSTERONE SYSTEM (RAAS) ANTAGONISTS ACE inhibitors ARBs Renin antagonists PHCMt774 Prof. Ashraf Abadi 5  ACE INHIBITORS DISCOVERY OF CAPTOPRIL, A RATIONAL APPROACH TO DRUG DESIGN Miguel Ondetti and David Cushman (BMS); Lasker`s Award 1998  Snake bites, kills due to severe hypotension, fractionation and investigation of the snake venom leads to the discovery of Teprotid.  Teprotid was isolated from the venom. It is an efficient antihypertensive agent, and potent ACE inhibitor. Teprotid, is a nonapeptide with proline the terminal AA : Glu-Trp-Pro-Arg-Pro-Glu-Ile-Pro-Pro. However, Teprotid and all its synthetic analogues failed in the clinics due to poor oral bioavailability. PHCMt774 Prof. Ashraf Abadi 6  DISCOVERY OF CAPTOPRIL, A RATIONAL APPROACH TO DRUG DESIGN  ACE structural and physiological properties are partially similar to another enzyme carboxypeptidase, both are metalloprotease, Zn2+ containing enzymes. Nevertheless, ACE detaches 2 AA from its substrate, carboxypeptidase detaches 1 AA from its substrate.  2-Benzylsuccinic acid is a known inhibitor to carboxypeptidase but not ACE.  A model was developed for the inhibition of carboxypeptidase by 2- benzylsuccinic acid. PHCMt774 Prof. Ashraf Abadi 7  DISCOVERY OF CAPTOPRIL, A RATIONAL APPROACH TO DRUG DESIGN  Prepare a hybrid dicarboxylic acid derivatives containing proline (from Teprotid) and succinic acid moiety (2-benzylsuccinic acid). O OH O OH O OH O OH O O O O N N N N HO HO HS HS CH3 CH3 O O Succinyl-L-proline 2-Methylsuccinyl-L-proline 3-Mercaptopropanoyl-L-proline Captopril Specific for ACE Additional methyl, Replace -COOH by - Add the methyl but 1/500 as active enhanced activity SH to enhance ,activity against as teprotid marginally binding to zinc. 1000X ACE increased as active as succynil- by 100 times L-proline and 10 x as IC50 1.7 nM teprotid. IC50 versus ACE is 200 nM PHCMt774 Prof. Ashraf Abadi 8 ACE INHIBITORS (PRILS) PHCMt774 Prof. Ashraf Abadi 9 ACE INHIBITORS (PRILS) PHCMt774 Prof. Ashraf Abadi 10  SAR OF ACE INHIBITORS  Proline or proline-like like moiety.  ACE inhibitors can be classified according to the group able to chelate Zinc: thiol containing, carboxylate containing, phosphonate containing.  Only two real drugs (Captopril and lisinopril).  All the others are prodrugs that require hydrolysis to produce the active form e.g. Enalapril gives Enalaprilat. Prodrugs will improve the pharmacokinetics and overcome the Zwitterionic nature of the drugs.  Enalaprilat is the most hydrophilic analogue and is the only one used by injections.  All chiral atoms are of the S configuration to mimic the natural substrate (Angiotensin I).  The phenylbutyroyl moiety allows interaction with a lipophilic pocket (Drug extension).  Captopril and Fosinopril are acidic, others are amphoteric.  Main side effects: skin rash, metallic taste (-SH) and dry cough (excessive bradykinin). PHCMt774 Prof. Ashraf Abadi 11 ACE INHIBITOR VERSUS ACE SUBSTRATE & DRUG-RECEPTOR INTERACTIONS H bonding anionic interaction O OH O NH N CH3 -O O hydrophobic interaction hydrophobic interaction chelation of zinc Enalaprilat PHCMt774 Prof. Ashraf Abadi 12  METABOLISM AND ASSAY OF CAPTOPRIL  Captopril is metabolized to its disulfide product. Other ACE excreted as their glucuronide conjugate with the acid function of the proline. Benazepril is the most liable to this type of metabolism.  Assay of captopril: Direct titration with iodine determining the end point potentiometrically. (Stability-indicating assay) PHCMt774 Prof. Ashraf Abadi 13 SYNTHESIS OF CAPTOPRIL PHCMt774 Prof. Ashraf Abadi 14 SYNTHESIS OF ENALAPRIL PHCMt774 Prof. Ashraf Abadi 15  ANGIOTENSIN RECEPTOR BLOCKERS (ARBS) AT1 ANTAGONISTS Discovery of Losartan CADD Overlapping features with Ang. II, weak antagonist, lead compound : IC50 = 4 x 10-5 mol/L., Extension of Phenyl is favorable to improve binding, CH2OH orally active PHCMt774 Prof. Ashraf Abadi 16 ANGIOTENSIN RECEPTOR BLOCKERS (ARBS, SARTANS) PHCMt774 Prof. Ashraf Abadi 17 ANGIOTENSIN RECEPTOR BLOCKERS (ARBS, SARTANS) PHCMt774 Prof. Ashraf Abadi 18  SAR OF ANGIOTENSIN II RECEPTOR BLOCKERS  Most are biphenylterazole or biphenylcarboxylic acid derivatives.  Tetrazole and carboxylic group are examples to non-classic bio-isosteres. Both groups are comparable in size, acidity, electronegativity but of different pharmacokinetics.  Nitrogenous imidazole, benzimidazole or open nitrogen containing side chain. Electrostatic potential map of losartan (left) and Telmisartan (right) PHCMt774 Prof. Ashraf Abadi 19  METABOLISM OF SARTANS  Olmesartan medoxomil is a prodrug that hydrolyzes to olmesartan.  Losartan is metabolized by oxidn of –CH2OH to –COOH which is an active metabolite (But losartan is NOT a prodrug !!). PHCMt774 Prof. Ashraf Abadi 20  LABORATORY SYNTHESIS OF LOSARTAN Br H 3C OH H 3C N Cl Cl N N N Cl N + N OH H OH CN CH3 (2-butyl-4(5)-chloro-1H-imidazol-5(4)-yl)methanol CN CN 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile 1 : 1 Desired underseired Two regioisomers Low yields NaN3/xylene/9 days Need purification Explosive inorganic azides H3C N Long reaction time! N Cl Can not be applied on OH industrial Scale. How to solve? N N N N H 32% yield PHCMt774 Prof. Ashraf Abadi 21 INDUSTRIAL SYNTHESIS OF LOSARTAN Br H 3C H 3C H3C 1. NaOH N CH3 N Cl H3C Sn CH3 Cl N 2. NaCNBH3 N N Cl N3 + N OH OH H CHO CN N N 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde N CN N SnMe3 Cl Desired (almost 100% yield) H3C Cl N OH Cl N N N 1. NaOH; OH 2. HCl N N H3C N N N N N N CPh3 H Losartan 70% yield PHCMt774 Prof. Ashraf Abadi 22  USES OF ARBS  Hypertension, CHF, LVH, LVD, acute myocardial infarction. May be used together with diuretics e.g. hydrochlorothiazide.  Advantages of AT1 antagonists over ACE inhibitors: Their effect is more specific on AT1 receptors, and less or none on bradykinin production or metabolism, so do not cause cough or angioedema. August 2018, worldwide warning to particular synthetic batches PHCMt774 Prof. Ashraf Abadi 23  ENTERSTO  Entresto, is an in a 1:1 mixture by molecule count of Sacubitril and Valsartan (24/26 mg, 49/51 mg and 97/103 mg) for the treatment of CHF. Sacubitril is a neprilysin inhibitor while valsartan is AT1 blocker. Such combination is mainly indicated for the treatment of CHF.  Sacubitril is a prodrug which is hydrolyzed by esterase to the dicarboxylic acid derivative. PHCMt774 Prof. Ashraf Abadi 24  ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR (ARNI)  Neprilysin is a zinc-dependent metalloprotease that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, bradykinin, ANP and BNP. PHCMt774 Prof. Ashraf Abadi 25  RENIN INHIBITORS: ALISKIREN (RASILEZ) Enhance affinity and Selectivity vs other aspartyl peptidases  (2S,4S,5S,7S)-5-Amino-N-(2-carbamoyl)-2-methylpropyl)-4-hydroxy-2-isopropyl-7- (4-methoxy-3-(3-methoxypropoxy) benzyl)-8-methylnonamide  Discovered by homology modeling and structure-based drug design.  Example of transition state analogues!! PHCMt774 Prof. Ashraf Abadi 26  RENIN INHIBITORS ALISKIREN (RASILEZ) PHCMt774 Prof. Ashraf Abadi 27