Design of [R-(Z)]-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2]octane-3-acetonitri le (SB 202026), a functionally selective azabicyclic muscarinic M1 agonist incorporating the N-methoxy imidoyl nitrile group as a novel ester bioisostere.
Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of muscarinic receptors located on nerve terminals while postsynaptic muscarinic M1 receptors appear to remain largely intact. Muscarinic agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic muscarinic agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisostere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile R-(+)-(Z)-5g which is a functionally selective muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)-(Z)-5g can be rationalized in terms of the relative affinity of the compound at muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.
Bromidge
S M
SM
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, Harlow, Essex, U.K.
Brown
F
F
Cassidy
F
F
Clark
M S
MS
Dabbs
S
S
Hadley
M S
MS
Hawkins
J
J
Loudon
J M
JM
Naylor
C B
CB
Orlek
B S
BS
Riley
G J
GJ
D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D004569:Electroencephalography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D014202:Tremor / Q000139:chemically induced
D007097:Imines; D018721:Muscarinic Agonists; D011812:Quinuclidines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D011994:Recombinant Proteins; C109640:sabcomeline